Piperazine compounds

ABSTRACT

A compound of formula (I), or a pharmaceutically acceptable salt, hydrate, complex or pro-drug thereof, 
                         
wherein one of R 1  and R 2  is H, and the other is selected from C 1-8 -alkyl, C 3-6 -cycloalkyl and C 1-8 -alkyl-C 5-10 -aryl; R 3  is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; R 9  is selected from the following:
 
                         
wherein:
     R 4  is selected from C 1-8 -alkyl and C 3-8 -cycloalkyl; G is selected from:  CH,  CMe and N; E is selected from: O, S,  SO 2 ,  NH,  NMe and N-oxide ( N→O); J and R are independently selected from:  CH, N and N-oxide ( N→O); and   R 41  is selected from amino, methylamino, dimethylamino, isopropylamino, isopropyl(methyl)amino, cyclopropylamino, cyclopropyl(methyl)amino, cyclopentylamino, morpholino, piperidin-1-yl, piperidin-1-ylmethyl, morpholinomethyl, 4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl, 1-morpholinoethyl, 1-(dimethylamino)ethyl, 1-(methylamino)ethyl, 4-fluoro-1-methylpyrrolidin-2-yl, 4,4-difluoropiperidin-1-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, pyridin-3-ylamino, pyridin-2-ylamino, 1-methylpyrrolidin-3-yl, methyl, isopropyl.   

     The invention further relates to pharmaceutical compositions comprising compounds of formula (I), and the use of such compounds in the treatment of various diseases.

RELATED APPLICATIONS

This application is a continuation of PCT/GB2009/000039, filed on Jan.7, 2009, which claims priority to GB patent application no. 0800338.6.filed on Jan. 9, 2008, which claims priority to GB application no.0808669.6, filed on May 13, 2008. The contents of each of theseapplications is incorporated herein by reference in their entirety.

The present invention relates to compounds that are inhibitors ofcysteine proteinases, pharmaceutical compositions containing saidcompounds, and their use in therapy. More specifically, but notexclusively, the invention relates to compounds that are inhibitors ofcathepsin K and related cysteine proteinases of the CA clan. Suchcompounds are particularly useful for the in vivo therapeutic treatmentof diseases in which participation of a cysteine proteinase isimplicated.

BACKGROUND TO THE INVENTION

Proteinases form a substantial group of biological molecules which todate constitute approximately 2% of all the gene products identifiedfollowing analysis of several completed genome sequencing programmes.Proteinases have evolved to participate in an enormous range ofbiological processes, mediating their effect by cleavage of peptideamide bonds within the myriad of proteins found in nature. thishydrolytic action is performed by initially recognising, then bindingto, particular three-dimensional electronic surfaces displayed by aprotein, which align the bond for cleavage precisely within theproteinase catalytic site. Catalytic hydrolysis then commences throughnucleophilic attach of the amide bond to be cleaved either via an aminoacid side-chain of the proteinase. Proteinases in which the attackingnucleophile is the thiol side-chain of a Cys residue are know ascysteine proteinases. The general classification of ‘cysteineproteinase’ contains many members found in a wide range of organismsfrom viruses, bacteria, protozoa, plants and fungi to mammals.

Cathepsin K and indeed many other crucial proteinases belong to thepapain-like CAC1 family. Cysteine proteinases are classified into‘clans’ based upon a similarity in the three-dimensional structure or aconserved arrangement of catalytic residues within the proteinaseprimary sequence. Additionally, ‘clans’ may be further classified into‘families; in which each proteinase shares a statistically significantrelationship with other members when comparing the portions or aminoacid sequence with constitute the parts responsible for the proteinaseactivity (see Barrett, A. J et al, in ‘Handbook of Proteolytic Enzymes’,Eds. Barrett, A. J., Rawlings, N. D., and Woessner, J. F. Publ. AcademicPress, 1998, for a thorough discussion).

To date, cysteine proteinases have been classified into five clans, CA,CB, CC, CD and CE (Barrett, A. S. et al, 1998). A proteinase from thetropical papaya fruit ‘papain’ forms the foundation of clan CA, whichcurrently contains over 80 distinct and complete entries in varioussequence databases, with many more expected from the current genomesequencing efforts. Proteinases of clan CA/family C1 have beenimplicated in a multitude of house-keeping roles and disease processes.e.g. human proteinases such as cathepsin K (osteoporosis,osteoarthritis), cathepsin S (multiple sclerosis, rheumatoid arthritis,autoimmune disorders), cathepsin L (metastases), cathepsin B(metastases, arthritis), cathepsin F (antigen processing), cathepsin V(T-cell selection), dipeptidyl peptidase I (granulocyte serineproteinase activation) or parasitic proteinases such as falcipain(malaria parasite Plasmodium falciparum) and cruzipain (Trypanosomacruzi infection). Recently a bacterial proteinase, staphylopain (S.aureus infection) has also been tentatively assigned to clan CA.

X-ray crystallographic structures are available for a range of the abovementioned proteinases in complex with a range of inhibitors e.g. papain(PDB entries, 1pad, 1pe6, 1pip, 1pop, 4pad, 5pad, 6pad, 1 ppp, 1the,1csb, 1huc), cathepsin K (1au0, 1au2, 1au3, 1au4, 1atk, 1mem, 1bgo,1ayw, 1ayu, 1n16, 1nlj, 1q6k, 1snk, 1tu6), cathepsin L (1 cs8, 1mhw),cathepsin S (1glo, 1ms6, 1npz), cathepsin V (1fh0), dipeptidyl peptidase(1jqp, 1k3b), cathepsin B (1gmy, 1csb), cathepsin F (1m6d), cruzain (arecombinant form of cruzipain see Eakin, A. E. et al, 268(9), 6115-6118,1993) (1ewp, 1aim, 2aim, 1F29, 1F2A, 1F2B, 1F2C), staphylopain (1cv8).Each of the structures displays a similar overall active-site topology,as would be expected by their ‘clan’ and ‘family’ classification andsuch structural similarity exemplifies one aspect of the difficultiesinvolved in discovering a selective inhibitor of cathepsin K suitablefor human use. However, subtle differences in terms of the depth andintricate shape of the active site groove of each CAC1 proteinase areevident, which may be exploited for selective inhibitor design.Additionally, many of the current substrate-based inhibitor complexes ofCAC1 family proteinases show a series of conserved hydrogen bondsbetween the inhibitor and the proteinase backbone, which contributesignificantly to inhibitor potency. Primarily a bidentate hydrogen-bondis observed between the proteinase Gly66 (C═O)/inhibitor N—H and theproteinase Gly66(NH)/inhibitor (C═O), where the inhibitor (C═O) and (NH)are provided by an amino acid residue NHCHRCO that constitutes the S2sub-site binding element within the inhibitor (see Berger, A. andSchecter, I. Philos. Trans. R. Soc. Lond. [Biol.], 257, 249-264, 1970for a description of proteinase binding site nomenclature). A furtherhydrogen-bond between the proteinase main-chain (C═O) of asparagine oraspartic acid (158 to 163, residue number varies between proteinases)and an inhibitor (N—H) is often observed, where the inhibitor (N—H) isprovided by the S1 sub-site binding element within the inhibitor. Thus,the motif X—NHCHRCO—NH—Y is widely observed amongst the prior artsubstrate-based inhibitors of CAC1 proteinases.

Cathepsin K is thought to be significant in diseases involving excessiveloss of bone or cartilage. Bone consists of a protein matrixincorporating hydroxyapatite crystals. About 90% of the structuralprotein of the matrix is type I collagen, with the remainder comprisingvarious non-collagenous proteins such as osteocalcin, proteoglycans,osteopontin, osteonectin, thrombospondin, fibronectin and bonesialoprotein.

Skeletal bone is not a static structure but continually undergoes acycle of bone resorption and replacement. Bone resorption is carried outby osteoclasts, which are multinuclear cells of haematopoietic lineage.Osteoclasts adhere to the bone surface and form a tight sealing zone.The membrane on the apical surface of the osteoclasts is folded so as tocreate a closed extracellular compartment between the osteoclast and thebone surface, which is acidified by proton pumps in the osteoclastmembrane. Proteolytic enzymes are secreted into the compartment from theosteoclast. The high acidity in the compartment causes thehydroxyapatite at the surface of the bone to be dissolved and theproteolytic enzymes break down the protein matrix causing a resorptionlacuna to be formed. Following bone resorption, osteoblasts produce anew protein matrix that is subsequently mineralised.

In disease states such as osteoporosis and Paget's disease, the boneresorption and replacement cycle is disrupted leading to a net loss ofbone with each cycle. This leads to weakening of the bone and thereforeto increased risk of bone fracture.

Cathepsin K is expressed at a high level in osteoclasts and is thereforethought to be essential for bone resorption. Thus, selective inhibitionof cathepsin K is likely to be effective in the treatment of diseasesinvolving excessive bone loss. These include osteoporosis, gingivaldiseases such as gingivitis and periodontitis, Paget's disease,hypercalaemia of malignancy and metabolic bone disease.

In addition to osteoclasts, high levels of cathepsin K are also found inchondroclasts from the synovium of osteoarthritic patients. It thereforeappears that cathepsin K inhibitors will be of use in the treatment ofdiseases involving matrix or cartilage degradation, in particularosteoarthritis and rheumatoid arthritis.

Elevated levels of cathepsin K are also found in metastatic neoplasticcells which suggests that cathepsin K inhibitors may also be useful fortreating certain neoplastic diseases.

In the prior art, the development of cysteine proteinase inhibitors forhuman use has recently been an area of intense activity (e.g. seeDeaton, D. N. and Kumar, S., Prog. Med. Chem. 42, 245-375, 2004;Bromine, D. and Kaleta, J., Curr. Pharm. Des., 8, 1639-1658, 2002; Kim,W. and Kang, K., Expert Opin. Ther. Patents, 12(3), 419-432, 2002;Leung-Toung, R. et al. Curr. Med. Chem., 9, 979-1002, 2002; Lecaille, F.et al., Chem. Rev., 102, 4459-4488, 2002; Hernandez, A. A. and Roush, W.R., Curr. Opin. Chem. Biol., 6, 459-465, 2002). Considering the CAC1family members, particular emphasis has been placed upon the developmentof inhibitors of human cathepsins, primarily cathepsin K (osteoporosis),cathepsin S (autoimmune disorders), cathepsin L (metastases), cathepsinB (metastases, arthritis), cathepsin F (antigen processing), cathepsin V(T-cell selection) and dipeptidyl peptidase I (granulocyte serineproteinase activation), through the use of peptide and peptidomimeticnitriles (e.g. see WO-A-03041649, WO-A-03037892, WO-A-03029200,WO-A-02051983, WO-A-02020485, US-A-20020086996, WO-A-01096285,WO-A-0109910, WO-A-0051998, WO-A-0119816, WO-A-9924460, WO-A-0049008,WO-A-0048992, WO-A-0049007, WO-A-0130772, WO-A-0055125, WO-A-0055126,WO-A-0119808, WO-A-0149288, WO-A-0147886), linear and cyclic peptide andpeptidomimetic ketones (e.g. see Veber, D. F. and Thompson, S. K., Curr.Opin. Drug Discovery Dev., 3(4), 362-369, 2000, WO-A-02092563,WO-A-02017924, WO-A-01095911, WO-A-0170232, WO-A-0178734, WO-A-0009653,WO-A-0069855, WO-A-0029408, WO-A-0134153 to WO-A-0134160, WO-A-0029408,WO-A-9964399, WO-A-9805336, WO-A-9850533), ketoheterocycles (e.g. seeWO-A-02080920, WO-A-03042197, WO-A-WO-A-03024924, WO-A-0055144,WO-A-0055124), monobactams (e.g. see WO-A-0059881, WO-A-9948911,WO-A-0109169), α-ketoamides (e.g. see WO-A-03013518), cyanoamides(WO-A-01077073, WO-A-01068645), dihydro pyrimidines (e.g. seeWO-A-02032879) and cyanoaminopyrimidines (e.g. see WO-A-03020278,WO-A-03020721).

The prior art describes potent in vitro inhibitors, but also highlightsthe many difficulties in developing a human therapeutic. For example,WO-A-9850533 and WO-A-0029408 describe compounds that may be referred toas cyclic ketones (e.g. 1′a-f) and are inhibitors of cysteineproteinases with a particular reference towards papain familyproteinases and as a most preferred embodiment, cathepsin K.WO-A-9850533 describes compounds subsequently detailed in the literatureas potent inhibitors of cathepsin K with good oral bioavailability(Witherington, J., ‘Tetrahydrofurans as Selective Cathepsin KInhibitors’, RSC meeting, Burlington House, London, 1999). The compoundsof WO-A-9850533 were reported to bind to cathepsin K through theformation of a reversible covalent bond between the tetrahydrofurancarbonyl and the active site catalytic cysteine residue (Witherington,J., 1999). Additionally, the same cyclic ketone compounds are describedin WO-A-9953039 as part of a wide-ranging description of inhibitors ofcysteine proteinases associated with parasitic diseases, with particularreference to the treatment of malaria by inhibition of falcipain.

The initial cyclic inhibitors of GSK were based upon potent, selectiveand reversible 3-amido-tetrahydrofuran-4-ones [1′a],3-amidopyrrolidin-4-ones [1′b], 4-amido-tetrahydropyran-3-ones [1′c],4-amidopiperidin-3-ones [1′d] and 4-amidoazepan-3-ones [1′e, 1′f] (shownabove) [see (a) Marquis, R. W. et al, J. Med. Chem. 2001, 44, 725, andreferences cited therein; (b) Marquis, R. W. et al, J. Med. Chem. 2001,44, 1380, and references cited therein; (c) Yamashita, D. S. et al, J.Med. Chem. 2006, 49(5), 1597-1612].

Further studies revealed that cyclic ketones [1′], in particular thefive-membered ring analogues [1′a] and [1′b], suffered fromconfigurational instability due to facile epimerisation at the centresituated a to the ketone [Marquis, R. W. et al, J. Med. Chem. 2001, 44,1380; Fenwick, A. E. et al, J. Bioorg. Med. Chem. Lett. 2001, 11, 199;WO 00/69855]. This precluded the pre-clinical optimisation of inhibitorsof formulae [1′a-d] and led to the development of the configurationallymore stable azepanone series [1′e], providing the cathepsin K inhibitorclinical candidate relacatib [1′f]. However, literature clearly statesthat azepanones are still prone to epimerisation and indeed relacatib[1′f] is reported to exist as a 9:1 thermodynamic mixture of 4-S and 4-Risomers [Yamashita, D. S. et al, J. Med. Chem., 2006, 49(5), 1597-1612].As an alternative to the ring expansion approach, alkylation of theα-carbon removes the ability of cyclic ketones [1′] to undergoα-enolisation and hence leads to configurational stability. However,studies have shown that α-methylation in the 3-amidopyrrolidin-4-one[1′b] system results in a substantial loss in potency versus cathepsin Kfrom K_(i,app)≈0.18 to 50 nM.

The cyclic ketone compounds of WO-A-0069855 are considered to be anadvance on compounds of WO-A-9850533 due to the presence of theβ-substituent on the cyclic ketone ring system that provides improvedchiral stability to the α-carbon of the cyclic ketone ring system.However, the compounds of WO-A-0069855 and indeed those of WO-A-9850533describe a requirement for the presence of the potentialhydrogen-bonding motif X—NHCHRCO—NH—Y that is widely observed amongstthe prior art substrate-based inhibitors of CAC1 proteinases.

More recent studies have investigated 5,5-bicyclic systems as inhibitorsof CAC1 proteinases, for example,N-(3-oxo-hexahydrocyclopenta[b]furan-3a-yl)acylamide bicyclic ketones[2′] [(a) Quibell, M.; Ramjee, M. K., WO 02/57246; (b) Watts, J. et al,Bioorg. Med. Chem. 2004, 12, 2903-2925],tetrahydrofuro[3,2-b]pyrrol-3-one based scaffolds [3′] [(a) Quibell, M.WO02/57270; (b) Quibell, M. et al, Bioorg. Med. Chem., 2004, 12,5689-5710], cis-6-oxohexahydro-2-oxa-1,4-diazapentalene andcis-6-oxo-hexahydropyrrolo[3,2-c]pyrazole based scaffolds [4′] [Wang, Y.et al, Bioorg. Med. Chem. Lett., 2005, 15, 1327-1331], andcis-hexahydropyrrolo[3,2-b]pyrrol-3-one based scaffolds [5′] [a)Quibell, M. WO04/07501; (b) Quibell, M. et al, Bioorg. Med. Chem., 2005,13, 609-625].

Studies have shown that the above-described 5,5-bicyclic systems exhibitpromising potency as inhibitors of a range of therapeutically attractivemammalian and parasitic CAC1 cysteinyl proteinase targets. Moreover, the5,5-bicyclic series are chirally stable due to a marked energeticpreference for a cis-fused rather than a trans-fused geometry. Thischiral stability provides a major advance when compared to monocyclicsystems that often show limited potential for preclinical developmentdue to chiral instability.

PCT applications WO-A-02057270 and WO-A-04007501 describe bicycliccompounds in which the chirality of the α-aminoketone is stabilised (fora review of energetic considerations within fused ring systems see (a)Toromanoff, E. Tetrahedron Report No 96, 36, 2809-2931, 1980; (b) Eliel,E. L. et. al. Stereochemistry of Organic Compounds, Wiley: New York,1-1267, 1994). These compounds do not contain the X—NHCHRCO—NH—Y motifand yet the compounds are highly potent inhibitors across a broad rangeof CAC1 cysteine proteinases. In particular, certain of the compoundsare potent and selective inhibitors of a range of mammalian andparasitic CAC1 proteinases.

More recently, Quibell, M. et al (Bioorg. Med. Chem. 12, 5689-5710,2004) disclosed two potent and selective cathepsin K inhibitors having atetrahydrofuro[3,2-b]pyrrol-3-one core, along with in vitro potency andin vitro selectivity data. Further kinetic parameters such as enzymeassociation (kon) and dissociation (koff) rates were disclosed, as wellas basic physiochemical parameters such as plasma and microsomestability, Caco-2 permeability and Log D (pH_(7.4)) measurements.

The present inventors have now discovered a small genus of6-alkyltetrahydrofuro[3,2-b]pyrrol-3-ones that exhibit potent in vitroinhibition versus human cathepsin K.

STATEMENT OF INVENTION

A first aspect of the invention relates to a compound of formula (I), ora pharmaceutically acceptable salt, hydrate, complex or pro-drugthereof,

wherein:one of R¹ and R² is H, and the other is selected from C₁₋₈-alkyl,C₃₋₆-cycloalkyl and C₁₋₈-alkyl-C₅₋₁₀-aryl;R³ is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl;R⁹ is selected from the following:

wherein:R⁴ is selected from C₁₋₈-alkyl and C₃₋₈-cycloalkyl;G is selected from:

-   -   CH₁,        CMe and N;        E is selected from:    -   O, S,        SO₂,        NH,        NMe and N-oxide (        N→O);        J and R are independently selected from:    -   CH, N and N-oxide (        N→O); and        R⁴¹ is selected from amino, methylamino, dimethylamino,        isopropylamino, isopropyl(methyl)amino, cyclopropylamino,        cyclopropyl(methyl)amino, cyclopentylamino, morpholino,        piperidin-1-yl, piperidin-1-ylmethyl, morpholinomethyl,        4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl,        1-morpholino ethyl, 1-(dimethylamino)ethyl,        1-(methylamino)ethyl, 4-fluoro-1-methylpyrrolidin-2-yl,        4,4-difluoropiperidin-1-yl, 1-methylpiperidin-4-yl,        pyridin-3-ylamino, pyridin-2-ylamino, 1-methylpyrrolidin-3-yl,        methyl, isopropyl.

As mentioned above, compounds of formula (I) exhibit surprisingly highefficacies for human cathepsin K. In addition, preferred compounds offormula (I) exhibit surprisingly good stability in plasma and microsomeassays.

A second aspect of the invention relates to a pharmaceutical orveterinary composition comprising a compound of formula (I) and apharmaceutically acceptable or veterinarily acceptable diluent,excipient and/or carrier.

A third aspect of the invention relates to a process for preparing apharmaceutical or veterinary composition as defined above, said processcomprising admixing a compound of the invention with a pharmaceuticallyacceptable or veterinarily acceptable diluent, excipient and/or carrier.

A fourth aspect of the invention relates to compounds of formula (I) foruse in medicine.

A fifth aspect of the invention relates to the use of a compound offormula (I) in the preparation of a medicament for treating a diseaseselected from osteoporosis, Paget's disease, Chagas's disease, malaria,gingival diseases, hypercalaemia, metabolic bone disease, diseasesinvolving matrix or cartilage degradation, and bone cancer disorderssuch as bone metastases and associated pain.

A sixth aspect of the invention relates to a method of inhibiting acysteine proteinase in a cell, said method comprising contacting saidcell with a compound of formula (I).

A seventh aspect of the invention relates to method of inhibiting acysteine proteinase in a subject, said method comprising administeringto the subject a pharmacologically effective amount of a compound offormula (I).

An eighth aspect of the invention relates to a method of treating adisease selected from osteoporosis, Paget's disease, Chagas's disease,malaria, gingival diseases, hypercalaemia, metabolic bone disease,diseases involving matrix or cartilage degradation, and bone cancerdisorders such as bone metastases and associated pain, in a subject,said method comprising administering to the subject a pharmacologicallyeffective amount of a compound of formula (I).

A ninth aspect of the invention relates to the use of a compoundaccording to the invention in an assay for identifying further candidatecompounds capable of inhibiting one or more cysteine proteinases.

A tenth aspect of the invention relates to the use of a compound offormula (I) in the validation of a known or putative cysteine proteinaseas a therapeutic target.

An eleventh aspect of the invention relates to a process of preparing acompound of formula (I).

DETAILED DESCRIPTION

The term ‘alkyl’ as applied herein includes stable straight and branchedchain aliphatic carbon chains which may be optionally substituted.Preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and any simpleisomers thereof. Suitable substituents include, for example, one or moreC₁₋₆ alkoxy, OH, COOH, COOMe, NH₂, NMe₂, NHMe, NO₂, CN, CF₃ and/or halogroups. Additionally, where the alkyl group contains two or morecontiguous carbon atoms, an alkene group (—CH═CH—) or alkyne group(—C≡C—) may be present. Furthermore, the alkyl group may optionallycontain one or more heteroatoms for example, to give ethers, thioethers,sulphones, sulphonamides, substituted amines, amidines, guanidines,carboxylic acids, carboxamides. If the heteroatom is located at a chainterminus then it is appropriately substituted with one or two hydrogenatoms. For example, the group CH₃—CH₂—O—CH₂—CH₂— is defined within‘alkyl’ as a C₄ alkyl that contains a centrally positioned heteroatomwhereas the group CH₃—CH₂—CH₂—CH₂— is defined within ‘alkyl’ as anunsubstituted C₄ alkyl.

Preferably, the alkyl group is a C₁₋₈ alkyl group, more preferably aC₁₋₆ group, even more preferably a C₁₋₄ alkyl group.

As used herein, the term “cycloalkyl” refers to a cyclic alkyl group(i.e. a carbocyclic ring) which may be substituted (mono- or poly-) orunsubstituted. Suitable substituents include, for example, one or moreC₁₋₆ alkyl, C₁₋₆ alkoxy, OH, COOH, COOMe, NH₂, NMe₂, NHMe, NO₂, CN, CF₃and/or halo groups. Preferably, the cycloalkyl group is a C₃₋₈cycloalkyl group, more preferably a C₃₋₆-cycloalkyl, even morepreferably a C₃₋₄ cycloalkyl group. Examples include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and the like. In addition, thecarbocyclic ring itself may optionally contain one or more heteroatoms,for example, to give a heterocycloalkyl group such as tetrahydrofuran,pyrrolidine, piperidine, piperazine or morpholine.

The term ‘alkyl-aryl’ as applied herein includes an alkyl group asdefined above in combination with an aryl group. The aryl group may bean aromatic ring, for, example, a stable 5 or 6-membered monocyclic or astable 9 or 10-membered bicyclic ring which is unsaturated. The arylgroup may optionally comprise one or more heteroatoms selected from O, Nand S. In addition, the aryl group may be optionally substituted, forexample, by one or more C₁₋₆ alkoxy, OH, COOH, COOMe, NH₂, NMe₂, NHMe,NO₂, CN, CF₃ and/or halo groups.

Preferably, the alkyl-aryl group is a C₁₋₈-alkyl-C₅₋₁₀-aryl group, evenmore preferably a C₁₋₈-alkyl-phenyl group. More preferably still, thealkyl-aryl group is selected from CH₂Ph and CH₂OCH₂Ph.

‘Halogen’ or ‘halo’ as applied herein encompasses F, Cl, Br, I.

‘Heteroatom’ as applied herein encompasses O, S, P and N, morepreferably, O, S and N.

The present invention includes all salts, hydrates, solvates, complexesand prodrugs of the compounds of this invention. The term “compound” isintended to include all such salts, hydrates, solvates, complexes andprodrugs, unless the context requires otherwise.

In particular, the skilled person will appreciate that the ketone groupof the bicycle core of compounds of formula (I) may exist in alternativeforms such as the hydrate (as shown below), and the invention extends toall such alternative forms.

Abbreviations and symbols commonly used in the peptide and chemical artsare used herein to describe compounds of the present invention,following the general guidelines presented by the IUPAC-IUB JointCommission on Biochemical Nomenclature as described in Eur. J. Biochem.,158, 9-, 1984. Compounds of formula (I) and the intermediates andstarting materials used in their preparation are named in accordancewith the IUPAC rules of nomenclature in which the characteristic groupshave decreasing priority for citation as the principle group.

In one preferred embodiment, the compound of the invention is of formulaIa

wherein R¹, R² and R⁹ are as defined above, and R³ is selected fromtert-butylmethyl, iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyland cyclohexyl.

In one preferred embodiment of the invention, one of R¹ and R² is H, andthe other is selected from methyl, ethyl, propyl, iso-propyl,tert-butyl, cyclopropyl, cyclopropylmethyl, iso-propylmethyl,tert-butylmethyl, CH₂OH, CH₂OMe, CH₂OCH₂Ph, CH₂Ph, CH₂F and CHF₂.

In another preferred embodiment, one of R¹ and R² is H, and the other isC₁₋₈-alkyl, optionally substituted by halo.

In one particularly preferred embodiment, one of R¹ and R² is H, and theother is selected from methyl, ethyl, iso-propyl and CHF₂.

In an even more preferred embodiment, one of R¹ and R² is H, and theother is methyl.

R³ is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl.

In one particularly preferred embodiment, R³ is cyclopentyl, tert-butylor 1-methylcyclopentyl.

In another preferred embodiment, R³ is selected from tert-butylmethyl,iso-propylmethyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl.

In another even more preferred embodiment, R³ is cyclopentyl ortert-butyl.

In one preferred embodiment, R³ is cyclohexyl such that the centralmoiety is the amino acid (S)-cyelohexylglycine.

In another preferred embodiment, R³ is cyclopentyl such that the centralmoiety is the amino acid (S)-cyclopentylglycine.

In another preferred embodiment, R³ is iso-propylmethyl such that thecentral moiety is the amino acid (S)-leucine.

In another preferred embodiment, R³ is tert-butyl such that the centralmoiety is the amino acid (S)-tert-butylglycine.

In another preferred embodiment, R³ is sec-butyl of S-configuration suchthat the central moiety is the amino acid (2S,3S)-isoleucine.

In another preferred embodiment, R³ is tert-butylmethyl such that thecentral moiety is the amino acid (S)-tert-butylalanine.

In another preferred embodiment, R³ is 1-methylcyclopentyl such that thecentral moiety is derived from the amino acid(S)-β-methylcyclopentylglycine((S)-2-amino-2-(1-methylcyclopentyl)acetic acid).

In a more preferred embodiment, the compound of the invention is offormula Ib

wherein R¹, R³ and R⁹ are as defined above.

In one preferred embodiment, with respect to the definition of R⁹:

G is selected as N;

E is selected from O, S and NH;

J and R are independently selected from CH and N.

In one particularly preferred embodiment, with respect to the definitionof R⁹:

G is selected as N;

J and R are CH;

E is selected as S;

In one preferred embodiment, R⁹ is chosen from:

In another preferred embodiment, R⁴¹ is selected from4-methylpiperazin-1-yl, 4-(2-methoxyethyl)piperazin-1-yl.

Even more preferably, R⁹ is chosen from:

In another preferred embodiment, R⁹ is chosen from:

wherein R⁴ is C₁₋₈-alkyl

More preferably, R⁴ is selected from methyl, ethyl and propyl. Even morepreferably, R⁴ is methyl.

In one highly preferred embodiment, the compound of the invention isselected from the following:

-   N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamide-   N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6    aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6    aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-5-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3    oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo    [3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,601)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6    aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6    aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—-((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,    2-1)]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4    (5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6    aH)-yl)-2-oxoethyl)-4 (4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)-thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamide-   N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]-pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,S6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo    [3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6H)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S))-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-(3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)benzamide-   N—-((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)    1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3    oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,60-1)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3    oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide-   N—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide-   N—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-benzyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide-   N—((S)-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide    and-   N—((S)-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide.

In one particularly preferred embodiment, the compound of the inventionis selected from Examples 1-30 and 38-42 described hereinbelow.

Even more preferably, the compound of the invention is selected fromExamples 1-8, 12, 16-18, 22-30 and 38-42 described hereinbelow.

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a compound of the invention admixed with one ormore pharmaceutically acceptable diluents, excipients or carriers. Otheractive materials may also be present, as may be considered appropriateor advisable for the disease or condition being treated or prevented.

Even though the compounds of the present invention (including theirpharmaceutically acceptable salts, esters and pharmaceuticallyacceptable solvates) can be administered alone, they will generally beadministered in admixture with a pharmaceutical carrier, excipient ordiluent, particularly for human therapy. The pharmaceutical compositionsmay be for human or animal usage in human and veterinary medicine.

Examples of such suitable excipients for the various different forms ofpharmaceutical compositions described herein may be found in the“Handbook of Pharmaceutical Excipients, 2^(nd) Edition, (1994), Editedby A Wade and P J Weller. The carrier, or, if more than one be present,each of the carriers, must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient.

Acceptable carriers or diluents for therapeutic use are well known inthe pharmaceutical art, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).

Examples of suitable carriers include lactose, starch, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like. Examplesof suitable diluents include ethanol, glycerol and water.

The choice of pharmaceutical carrier, excipient or diluent can beselected with regard to the intended route of administration andstandard pharmaceutical practice. The pharmaceutical compositions maycomprise as, or in addition to, the carrier, excipient or diluent anysuitable binder(s), lubricant(s), suspending agent(s), coating agent(s),solubilising agent(s).

Examples of suitable binders include starch, gelatin, natural sugarssuch as glucose, anhydrous lactose, free-flow lactose, beta-lactose,corn sweeteners, natural and synthetic gums, such as acacia, tragacanthor sodium alginate, carboxymethyl cellulose and polyethylene glycol.

Examples of suitable lubricants include sodium oleate, sodium stearate,magnesium stearate, sodium benzoate, sodium acetate, sodium chloride andthe like.

Preservatives, stabilizers, dyes and even flavoring agents may beprovided in the pharmaceutical composition. Examples of preservativesinclude sodium benzoate, sorbic acid and esters of p-hydroxybenzoicacid. Antioxidants and suspending agents may be also used.

According to a further aspect of the invention, there is provided aprocess for the preparation of a pharmaceutical or veterinarycomposition as described above, the process comprising bringing theactive compound(s) into association with the carrier, for example byadmixture.

In general, the formulations are prepared by uniformly and intimatelybringing into association the active agent with liquid carriers orfinely divided solid carriers or both, and then if necessary shaping theproduct. The invention extends to methods for preparing a pharmaceuticalcomposition comprising bringing a compound of general formula (I) inconjunction or association with a pharmaceutically or veterinarilyacceptable carrier or vehicle.

Salts/Esters

The compounds of the invention can be present as salts or esters, inparticular pharmaceutically and veterinarily acceptable salts or esters.

Pharmaceutically acceptable salts of the compounds of the inventioninclude suitable acid addition or base salts thereof. A review ofsuitable pharmaceutical salts may be found in Berge et al, J Pharm Sci,66, 1-19 (1977). Salts are formed, for example with strong inorganicacids such as mineral acids, e.g. hydrohalic acids such ashydrochloride, hydrobromide and hydroiodide, sulphuric acid, phosphoricacid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate andsulphonic acids; with strong organic carboxylic acids, such asalkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted orsubstituted (e.g., by halogen), such as acetic acid; with saturated orunsaturated dicarboxylic acids, for example oxalic, malonic, succinic,maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylicacids, for example ascorbic, glycolic, lactic, malic, tartaric or citricacid; with aminoacids, for example aspartic or glutamic acid; withbenzoic acid; or with organic sulfonic acids, such as (C₁-C₄)-alkyl- oraryl-sulfonic acids which are unsubstituted or substituted (for example,by a halogen) such as methane- or p-toluene sulfonic acid. Salts whichare not pharmaceutically or veterinarily acceptable may still bevaluable as intermediates.

Preferred salts include, for example, acetate, trifluoroacetate,lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate,adipate, alginate, aspartate, benzoate, butyrate, digluconate,cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate,hexanoate, fumarate, nicotinate, palmoate, pectinate,3-phenylpropionate, picrate, pivalate, proprionate, tartrate,lactobionate, pivolate, camphorate, undecanoate and succinate, organicsulphonic acids such as methanesulphonate, ethanesulphonate,2-hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenesulphonate,benzenesulphonate, p-chlorobenzenesulphonate and p-toluenesulphonate;and inorganic acids such as hydrochloride, hydrobromide, hydroiodide,sulphate, bisulphate, hemisulphate, thiocyanate, persulphate, phosphoricand sulphonic acids.

Esters are formed either using organic acids or alcohols/hydroxides,depending on the functional group being esterified. Organic acidsinclude carboxylic acids, such as alkanecarboxylic acids of 1 to 12carbon atoms which are unsubstituted or substituted (e.g., by halogen),such as acetic acid; with saturated or unsaturated dicarboxylic acid,for example oxalic, malonic, succinic, maleic, fumaric, phthalic ortetraphthalic; with hydroxycarboxylic acids, for example ascorbic,glycolic, lactic, malic, tartaric or citric acid; with aminoacids, forexample aspartic or glutamic acid; with benzoic acid; or with organicsulfonic acids, such as (C₁-C₄)-alkyl- or aryl-sulfonic acids which areunsubstituted or substituted (for example, by a halogen) such asmethane- or p-toluene sulfonic acid. Suitable hydroxides includeinorganic hydroxides, such as sodium hydroxide, potassium hydroxide,calcium hydroxide, aluminium hydroxide. Alcohols include alkanealcoholsof 1-12 carbon atoms which may be unsubstituted or substituted, e.g. bya halogen).

Enantiomers/Tautomers

In all aspects of the present invention previously discussed, theinvention includes, where appropriate all enantiomers, diastereoisomersand tautomers of the compounds of the invention. The person skilled inthe art will recognise compounds that possess optical properties (one ormore chiral carbon atoms) or tautomeric characteristics. Thecorresponding enantiomers and/or tautomers may be isolated/prepared bymethods known in the art.

Enantiomers are characterised by the absolute configuration of theirchiral centres and described by the R- and S-sequencing rules of Calm,Ingold and Prelog. Such conventions are well known in the art (e.g. see‘Advanced Organic Chemistry’, 3rd edition, ed. March, J., John Wiley andSons, New York, 1985).

Compounds of the invention containing a chiral centre may be used as aracemic mixture, an enantiomerically enriched mixture, or the racemicmixture may be separated using well-known techniques and an individualenantiomer may be used alone.

Stereo and Geometric Isomers

Some of the compounds of the invention may exist as stereoisomers and/orgeometric isomers—e.g. they may possess one or more asymmetric and/orgeometric centres and so may exist in two or more stereoisomeric and/orgeometric forms. The present invention contemplates the use of all theindividual stereoisomers and geometric isomers of those inhibitoragents, and mixtures thereof. The terms used in the claims encompassthese forms, provided said forms retain the appropriate functionalactivity (though not necessarily to the same degree).

The present invention also includes all suitable isotopic variations ofthe agent or a pharmaceutically acceptable salt thereof. An isotopicvariation of an agent of the present invention or a pharmaceuticallyacceptable salt thereof is defined as one in which at least one atom isreplaced by an atom having the same atomic number but an atomic massdifferent from the atomic mass usually found in nature. Examples ofisotopes that can be incorporated into the agent and pharmaceuticallyacceptable salts thereof include isotopes of hydrogen, carbon, nitrogen,oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. Certainisotopic variations of the agent and pharmaceutically acceptable saltsthereof, for example, those in which a radioactive isotope such as ³H or¹⁴C is incorporated, are useful in drug and/or substrate tissuedistribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with isotopes such as deuterium,i.e., ²H, may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example, increased in vivo half-life orreduced dosage requirements and hence may be preferred in somecircumstances. For example, the invention includes compounds of generalformula (I) where any hydrogen atom has been replaced by a deuteriumatom. Isotopic variations of the agent of the present invention andpharmaceutically acceptable salts thereof of this invention cangenerally be prepared by conventional procedures using appropriateisotopic variations of suitable reagents.

Prodrugs

The invention further includes the compounds of the present invention inprodrug form, i.e. covalently bonded compounds which release the activeparent drug according to general formula (I) in vivo. Such prodrugs aregenerally compounds of the invention wherein one or more appropriategroups have been modified such that the modification may be reversedupon administration to a human or mammalian subject. Reversion isusually performed by an enzyme naturally present in such subject, thoughit is possible for a second agent to be administered together with sucha prodrug in order to perform the reversion in vivo. Examples of suchmodifications include ester (for example, any of those described above),wherein the reversion may be carried out be an esterase etc. Other suchsystems will be well known to those skilled in the art.

A prodrug may for example constitute a ketal or hemiketal derivative ofthe exocyclic ketone functionality present in the6-alkyltetrahydrofuro[3,2-b]pyrrol-3-one scaffold.

Solvates

The present invention also includes solvate forms of the compounds ofthe present invention. The terms used in the claims encompass theseforms.

Polymorphs

The invention further relates to the compounds of the present inventionin their various crystalline forms, polymorphic forms and (an)hydrousforms. It is well established within the pharmaceutical industry thatchemical compounds may be isolated in any of such forms by slightlyvarying the method of purification and or isolation form the solventsused in the synthetic preparation of such compounds.

Assays

Another aspect of the invention relates to the use of a compound of theinvention as defined hereinabove in an assay for identifying furthercandidate compounds that influence the activity of a cysteineproteinase.

Preferably, the assay is capable of identifying candidate compounds thatare capable of inhibiting one or more CAC1 cysteine proteinases.

More preferably, the assay is a competitive binding assay.

Preferably, the candidate compound is generated by conventional SARmodification of a compound of the invention.

As used herein, the term “conventional SAR modification” refers tostandard methods known in the art for varying a given compound by way ofchemical derivatisation.

Thus, in one aspect, the identified compound may act as a model (forexample, a template) for the development of other compounds. Thecompounds employed in such a test may be free in solution, affixed to asolid support, borne on a cell surface, or located intracellularly. Theabolition of activity or the formation of binding complexes between thecompound and the agent being tested may be measured.

The assay of the present invention may be a screen, whereby a number ofagents are tested. In one aspect, the assay method of the presentinvention is a high through-put screen.

This invention also contemplates the use of competitive drug screeningassays in which neutralising antibodies capable of binding a compoundspecifically compete with a test compound for binding to a compound.

Another technique for screening provides for high throughput screening(HTS) of agents having suitable binding affinity to the substances andis based upon the method described in detail in WO 84/03564.

It is expected that the assay methods of the present invention will besuitable for both small and large-scale screening of test compounds aswell as in quantitative assays.

Preferably, the competitive binding assay comprises contacting acompound of the invention with a cysteine proteinase in the presence ofa known substrate of said enzyme and detecting any change in theinteraction between said cysteine proteinase and said known substrate.

A further aspect of the invention provides a method of detecting thebinding of a ligand to a cysteine proteinase, said method comprising thesteps of:

-   (i) contacting a ligand with cysteine proteinase in the presence of    a known substrate of said enzyme;-   (ii) detecting any change in the interaction between said enzyme and    said known substrate;    and wherein said ligand is a compound of the invention.

One aspect of the invention relates to a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain; and-   (c) preparing a quantity of said one or more ligands.

Another aspect of the invention provides a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain; and-   (c) preparing a pharmaceutical composition comprising said one or    more ligands.

Another aspect of the invention provides a process comprising the stepsof:

-   (a) performing an assay method described hereinabove;-   (b) identifying one or more ligands capable of binding to a ligand    binding domain;-   (c) modifying said one or more ligands capable of binding to a    ligand binding domain;-   (d) performing the assay method described hereinabove;-   (e) optionally preparing a pharmaceutical composition comprising    said one or more ligands.

The invention also relates to a ligand identified by the methoddescribed hereinabove.

Yet another aspect of the invention relates to a pharmaceuticalcomposition comprising a ligand identified by the method describedhereinabove.

Another aspect of the invention relates to the use of a ligandidentified by the method described hereinabove in the preparation of apharmaceutical composition for use in the treatment of one or moredisorders selected from osteoporosis, Paget's disease, Chagas's disease,malaria, gingival disease such as gingivitis or periodontitis,hypercalaemia, metabolic bone disease and diseases involving matrix orcartilage degradation, such as osteoarthritis, rheumatoid arthritis andneoplastic diseases.

The above methods may be used to screen for a ligand useful as aninhibitor of one or more cysteine proteinases.

Compounds of general formula (I) are useful both as laboratory tools andas therapeutic agents. In the laboratory certain compounds of theinvention are useful in establishing whether a known or newly discoveredcysteine proteinase contributes a critical or at least significantbiochemical function during the establishment or progression of adisease state, a process commonly referred to as ‘target validation’.

According to a further aspect of the invention, there is provided amethod of validating a known or putative cysteine proteinase as atherapeutic target, the method comprising:

(a) assessing the in vitro binding of a compound as described above toan isolated known or putative cysteine proteinase, providing a measureof potency; and optionally, one or more of the steps of:

(b) assessing the binding of the compound to closely related homologousproteinases of the target and general house-keeping proteinases (e.g.trypsin) to provide a measure of selectivity;

-   (c) monitoring a cell-based functional marker of a particular    cysteine proteinase activity, in the presence of the compound; and-   (d) monitoring an animal model-based functional marker of a    particular cysteine proteinase activity in the presence of the    compound.

The invention therefore provides a method of validating a known orputative cysteine proteinase as a therapeutic target. Differingapproaches and levels of complexity are appropriate to the effectiveinhibition and ‘validation’ of a particular target. In the firstinstance, the method comprises assessing the in vitro binding of acompound of general formula (I) to an isolated known or putativecysteine proteinase, providing a measure of ‘potency’. An additionalassessment of the binding of a compound of general formula (I) toclosely related homologous proteinases of the target and generalhouse-keeping proteinases (e.g. trypsin) provides a measure of‘selectivity’. A second level of complexity may be assessed bymonitoring a cell-based functional marker of a particular cysteineproteinase activity, in the presence of a compound of general formula(I). For example, an ‘osteoclast resorption assay’ has been utilised asa cell-based secondary in vitro testing system for monitoring theactivity of cathepsin K and the biochemical effect of proteinaseinhibitors (e.g. see WO-A-9850533). An ‘MHC-II processing—T-cellactivation assay’ has been utilised as a cell-based secondary in vitrotesting system for monitoring the activity of cathepsin S and thebiochemical effect of proteinase inhibitors (Shi, G-P., et al, Immunity,10, 197-206, 1999). When investigating viral or bacterial infectionssuch a marker could simply be a functional assessment of viral (e.g.count of mRNA copies) or bacterial loading and assessing the biochemicaleffect of proteinase inhibitors. A third level of complexity may beassessed by monitoring an animal model-based functional marker of aparticular cysteine proteinase activity, in the presence of a compoundof general formula (I). For example, murine models of Leishmaniainfection, P. vinckei infection, malaria (inhibition of falcipain) andT. cruzi infection (cruzipain), indicate that inhibition of cysteineproteinases that play a key role in pathogen propagation is effective inarresting disease symptoms, ‘validating’ said targets.

The invention therefore extends to the use of a compound of generalformula (I) in the validation of a known or putative cysteine proteinaseas a therapeutic target.

Biological Activity

The compounds of the present invention are structurally distinct fromthe prior art (e.g. WO-A-02057270; Quibell, M. et. al., Bioorg. Med.Chem. 13, 609-625, 2005; Quibell M, et al Bioorg. Med. Chem., 12,5689-5710, 2004) in that a 6-alkyl substituent is an integral part ofthe present invention and this provides surprisingly high efficacies forhuman cathepsin K. Indeed, all of the compounds of the present inventionprepared to date exhibit potent in vitro inhibition versus humancathepsin K with Ki<10 nM. In contrast, the majority of the eighty-twoprior art compounds detailed in WO-A-02057270 are significantly lesspotent against human cathepsin K than the compounds of the presentinvention and in the majority of examples greater than 1000-fold lesspotent (for example see table 2). The closest prior art, compound (42)(Quibell, M. et. al., Bioorg. Med. Chem. 13, 609-625, 2005), exhibits a3.5-fold improvement in in vitro potency against human cathepsin K uponaddition of a 6-(R)-Me substituent (EXAMPLE 1); an 11.6-fold improvementupon addition of a 6-(S)-Me substituent (EXAMPLE 5); a 5.7-foldimprovement upon addition of a 6-(R)—CHF₂ substituent (EXAMPLE 8) and a10.9-fold improvement upon addition of a 6-(S)—CHF₂ substituent (EXAMPLE12). Introduction of other structural changes, that are integral to thepresent invention, when compared to closest prior art compound (42)(Quibell, M. et. al., Bioorg. Med. Chem. 13, 609-625, 2005), e.g.changing the P2 aminoacid from L-leucine to L-cyclopentylglycine andaddition of a 6-(R)-Me substituent gives a 8.7-fold improvement (EXAMPLE4); whilst addition of a 6-(S)-Me substituent gives a 24.9-foldimprovement upon (EXAMPLE 7); whilst addition of a 6-(S)-Et substituentgives a 22.9-fold improvement upon (EXAMPLE 29); whilst addition of a6-(R)-Et substituent gives a 7.3-fold improvement upon (EXAMPLE 27);whilst addition of a 6-(S)-iPr substituent gives a 18.9-fold improvementupon (EXAMPLE 30); whilst addition of a 6-(R)-iPr substituent gives a5.8-fold improvement upon (EXAMPLE 28). Preferably, the compoundsexhibit in vitro inhibition versus human cathepsin K with Ki<10 nM, morepreferably <5 nM, even more preferably <2 nM and more preferably still<1 nM. The compounds of the invention exhibit high selectivity againstother mammalian cathepsins displaying little or no inhibitory activityfor cathepsins S, L, B and V at 1 μM compound.

Therapeutic Use

Compounds of general formula (I) are useful for the in vivo treatment orprevention of diseases in which participation of a cysteine proteinaseis implicated.

Preferably, the compound of general formula I is selective for cathepsinK. As used herein, the term “selective for cathepsin K” means that theinhibitor is selective for cathepsin K over one or more other mammalianCAC1 cysteinyl proteinases for example cathepsin S, cathepsin L,cathepsin F, cathepsin B and cathepsin V. Preferably, the inhibitorexhibits a selectivity ratio for cathepsin K over other mammalian CAC1cysteinyl proteinases of greater than 2-fold, more preferably greaterthan 5-fold, more preferably greater than 10-fold, even more preferablygreater than 25-fold, more preferably still, greater than 50-fold or100-fold.

According to a further aspect of the invention, there is provided acompound of general formula (I) for use in medicine, especially forpreventing or treating diseases in which the disease pathology may bemodified by inhibiting a cysteine proteinase.

According to a further aspect of the invention, there is provided theuse of a compound of general formula (I) in the preparation of amedicament for preventing or treating diseases in which the diseasepathology may be modified by inhibiting a cysteine proteinase.

Certain cysteine proteinases function in the normal physiologicalprocess of protein degradation in animals, including humans, e.g. in thedegradation of connective tissue. However, elevated levels of theseenzymes in the body can result in pathological conditions leading todisease. Thus, cysteine proteinases have been implicated in variousdisease states, including but not limited to, infections by Pneumocystiscarinii, Trypsanoma cruzi, Trypsanoma brucei brucei and Crithidiafusiculata; as well as in osteoporosis, osteoarthritis, rheumatoidarthritis, multiple sclerosis, chronic pain, autoimmunity,schistosomiasis, malaria, tumour metastasis, metachromaticleukodystrophy, muscular dystrophy, amytrophy, and the like (seeWO-A-9404172 and EP-A-0603873 and references cited therein).Additionally, a secreted bacterial cysteine proteinase from S. Aureuscalled staphylopain has been implicated as a bacterial virulence factor(Potempa, J., et al. J. Biol. Chem., 262(6), 2664-2667, 1998).

The invention is useful in the prevention and/or treatment of each ofthe disease states mentioned or implied above. The present inventionalso is useful in a method of treatment or prevention of diseases causedby pathological levels of cysteine proteinases, particularly cysteineproteinases of the papain superfamily, which methods compriseadministering to an animal, particularly a mammal, most particularly ahuman, in need thereof a compound of the present invention. The presentinvention particularly provides methods for treating diseases in whichcysteine proteinases are implicated, including infections byPneumocystis carinii, Trypsanoma cruzi, Trypsanoma brucei, Leishmanianiexicana, Clostridium histolyticum, Staphylococcus aureus,foot-and-mouth disease virus and Crithidia fusiculata; as well as inosteoporosis, osteoarthritis, rheumatoid arthritis, multiple sclerosis,chronic pain, autoimmunity, schistosomiasis, malaria, tumour metastasis,metachromatic leukodystrophy, muscular dystrophy, amytrophy.

Inhibitors of cathepsin K, particularly cathepsin K-specific compounds,are useful for the treatment of osteoporosis, Paget's disease, gingivaldiseases such as gingivitis and periodontitis, hypercalaemia ofmalignancy, metabolic bone disease, diseases involving matrix orcartilage degradation, in particular osteoarthritis and rheumatoidarthritis and neoplastic diseases.

Preferred features for each aspect of the invention are as for eachother aspect mutatis mutandis.

Administration

The pharmaceutical compositions of the present invention may be adaptedfor rectal, nasal, intrabronchial, topical (including buccal andsublingual), vaginal or parenteral (including subcutaneous,intramuscular, intravenous, intraarterial and intradermal),intraperitoneal or intrathecal administration. Preferably theformulation is an orally administered formulation. The formulations mayconveniently be presented in unit dosage form, i.e., in the form ofdiscrete portions containing a unit dose, or a multiple or sub-unit of aunit dose. By way of example, the formulations may be in the form oftablets and sustained release capsules, and may be prepared by anymethod well known in the art of pharmacy.

Formulations for oral administration in the present invention may bepresented as: discrete units such as capsules, gentiles, drops, cachets,pills or tablets each containing a predetermined amount of the activeagent; as a powder or granules; as a solution, emulsion or a suspensionof the active agent in an aqueous liquid or a non-aqueous liquid; or asan oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or asa bolus etc. Preferably, these compositions contain from 1 to 250 mg andmore preferably from 10-100 mg, of active ingredient per dose.

For compositions for oral administration (e.g. tablets and capsules),the term “acceptable carrier” includes vehicles such as commonexcipients e.g. binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose,ethylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers,for example corn starch, gelatin, lactose, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride andalginic acid; and lubricants such as magnesium stearate, sodium stearateand other metallic stearates, glycerol stearate stearic acid, siliconefluid, talc waxes, oils and colloidal silica. Flavouring agents such aspeppermint, oil of wintergreen, cherry flavouring and the like can alsobe used. It may be desirable to add a colouring agent to make the dosageform readily identifiable. Tablets may also be coated by methods wellknown in the art.

A tablet may be made by compression or moulding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active agent in a free flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, preservative, surface-active or dispersingagent. Moulded tablets may be made by moulding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.The tablets may be optionally be coated or scored and may be formulatedso as to provide slow or controlled release of the active agent.

Other formulations suitable for oral administration include lozengescomprising the active agent in a flavoured base, usually sucrose andacacia or tragacanth; pastilles comprising the active agent in an inertbase such as gelatin and glycerin, or sucrose and acacia; andmouthwashes comprising the active agent in a suitable liquid carrier.

Other forms of administration comprise solutions or emulsions which maybe injected intravenously, intraarterially, intrathecally,subcutaneously, intradermally, intraperitoneally or intramuscularly, andwhich are prepared from sterile or sterilisable solutions. Injectableforms typically contain between 10-1000 mg, preferably between 10-250mg, of active ingredient per dose.

The pharmaceutical compositions of the present invention may also be inform of suppositories, pessaries, suspensions, emulsions, lotions,ointments, creams, gels, sprays, solutions or dusting powders.

An alternative means of transdermal administration is by use of a skinpatch. For example, the active ingredient can be incorporated into acream consisting of an aqueous emulsion of polyethylene glycols orliquid paraffin. The active ingredient can also be incorporated, at aconcentration of between 1 and 10% by weight, into an ointmentconsisting of a white wax or white soft paraffin base together with suchstabilisers and preservatives as may be required.

Dosage

A person of ordinary skill in the art can easily determine anappropriate dose of one of the instant compositions to administer to asubject without undue experimentation. Typically, a physician willdetermine the actual dosage which will be most suitable for anindividual patient and it will depend on a variety of factors includingthe activity of the specific compound employed, the metabolic stabilityand length of action of that compound, the age, body weight, generalhealth, sex, diet, mode and time of administration, rate of excretion,drug combination, the severity of the particular condition, and theindividual undergoing therapy. The dosages disclosed herein areexemplary of the average case. There can of course be individualinstances where higher or lower dosage ranges are merited, and such arewithin the scope of this invention.

In accordance with this invention, an effective amount of a compound ofgeneral formula (I) may be administered to inhibit the proteinaseimplicated with a particular condition or disease. Of course, thisdosage amount will further be modified according to the type ofadministration of the compound. For example, to achieve an “effectiveamount” for acute therapy, parenteral administration of a compound ofgeneral formula (I) is preferred. An intravenous infusion of thecompound in 5% dextrose in water or normal saline, or a similarformulation with suitable excipients, is most effective, although anintramuscular bolus injection is also useful. Typically, the parenteraldose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and20 mg/kg, in a manner to maintain the concentration of drug in theplasma at a concentration effective to inhibit a cysteine proteinase.The compounds may be administered one to four times daily at a level toachieve a total daily dose of about 0.4 to about 400 mg/kg/day. Theprecise amount of an inventive compound which is therapeuticallyeffective, and the route by which such compound is best administered, isreadily determined by one of ordinary skill in the art by comparing theblood level of the agent to the concentration required to have atherapeutic effect. Prodrugs of compounds of the present invention maybe prepared by any suitable method. For those compounds in which theprodrug moiety is a ketone functionality, specifically ketals and/orhemiketals, the conversion may be effected in accordance withconventional methods.

The compounds of this invention may also be administered orally to thepatient, in a manner such that the concentration of drug is sufficientto inhibit bone resorption or to achieve any other therapeuticindication as disclosed herein. Typically, a pharmaceutical compositioncontaining the compound is administered at an oral dose of between about0.1 to about 50 mg/kg in a manner consistent with the condition of thepatient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.

No unacceptable toxicological effects are expected when compounds of thepresent invention are administered in accordance with the presentinvention. The compounds of this invention, which may have goodbioavailability, may be tested in one of several biological assays todetermine the concentration of a compound which is required to have agiven pharmacological effect.

Combinations

In a particularly preferred embodiment, the one or more compounds of theinvention are administered in combination with one or more other activeagents, for example, existing drugs available on the market. In suchcases, the compounds of the invention may be administered consecutively,simultaneously or sequentially with the one or more other active agents.

Drugs in general are more effective when used in combination. Inparticular, combination therapy is desirable in order to avoid anoverlap of major toxicities, mechanism of action and resistancemechanism(s). Furthermore, it is also desirable to administer most drugsat their maximum tolerated doses with minimum time intervals betweensuch doses. The major advantages of combining chemotherapeutic drugs arethat it may promote additive or possible synergistic effects throughbiochemical interactions and also may decrease the emergence ofresistance.

Beneficial combinations may be suggested by studying the inhibitoryactivity of the test compounds with agents known or suspected of beingvaluable in the treatment of a particular disorder. This procedure canalso be used to determine the order of administration of the agents,i.e. before, simultaneously, or after delivery. Such scheduling may be afeature of all the active agents identified herein.

Synthesis

Synthesis of 5,5-Bicyclic Core

One aspect of the invention relates to a process of preparing a compoundof formula (I) as defined above, said process comprising oxidation of acompound of formula (II).

Any suitable oxidising agent may be used to convert the secondaryalcohol group of (II) into the corresponding ketone (I). Suitableoxidising agents will be familiar to the skilled artisan. By way ofexample, the oxidation may be carried out via a Dess-Martin periodinanereaction [Dess, D. B. et al, J. Org. Chem. 1983, 48, 4155; Dess, D. B.et al, J. Am. Chem. Soc. 1991, 113, 7277], or via a Swern oxidation[Mancuso, A. J. et al, J. Org. Chem. 1978, 43, 2480]. Alternatively, theoxidation can be carried out using SO₃/pyridine/Et₃N/DMSO [Parith, J. R.et al, J. Am. Chem., Soc. 1967, 5505; U.S. Pat. No. 3,444,216, Parith,J. R. et al,], P₂O₅/DMSO or P₂O₅/Ac₂O [Christensen, S. M. et al, OrganicProcess Research and Development, 2004, 8, 777]. Other alternativeoxidation reagents include activated dimethyl sulphoxide [Mancuso, A.J., Swern, D. J., Synthesis, 1981, 165], pyridinium chlorochromate[Pianeatelli, G. et al, Synthesis, 1982, 245] and Jones' reagent [Vogel,A, I., Textbook of Organic Chemistry, 6^(th) Edition].

More preferably, the process comprises treating a compound of formula(II) with Dess-Martin periodinane. Preferably, the reaction is carriedout using dichloromethane as solvent.

In one preferred embodiment, the process of the invention comprises thestep of converting a compound of formula (III) into a compound offormula (II) through standard amide bond formation betweenR⁹CONHCH(R³)COOH and the compound of formula (III; R⁵═H) with a suitablecarboxylic acid activating agent.

where R⁵ is a protecting group or hydrogen.

In one preferred embodiment, protecting group R⁵ is selected frombenzyloxycarbonyl, tert-butoxycarbonyl, fluoren-9-ylmethoxycarbonyl,1-(biphenyl-4-yl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxylbenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, allyloxycarbonyland trichloroethoxycarbonyl.

More preferably, R⁵ is benzyloxycarbonyl, tert-butoxycarbonyl (Boc) orflouren-9-ylmethoxycarbonyl (Fmoc).

In another preferred embodiment R⁵ is H.

In a more preferred embodiment the process of the invention comprisesthe step of converting a compound of formula (IV) into a compound offormula (III; R⁵═H)

where Lg is a leaving group such as tosylate, mesylate or bromide and R⁵is as previously defined.

In an even more preferred embodiment the process of the inventioncomprises the step of converting a compound of formula (IVa; R⁵═H) intoa compound of formula (IIIa) or a compound of formula (IVb) into acompound of formula (IIIb)

Alternatively, a compound of formula (IVc) may be converted into acompound of formula (IIIb) via the intermediate inverted bromide (IVd)

For compounds of formulae (IIIa) and (IIIb) wherein R¹ or R² are methylthe displacement of tosylate or bromide is typically performed using anexcess of a variety of suitable alkylmetal reagents e.g. a mixture of 2eq. MeLi to 1 eq. Cu(I)Br that generates Li—Cu(Me)₂ as the activespecies. This displacement proceeds with retention of configuration. Byanalogy a similar displacement with alternative alkylmetal reagents maybe performed to give for example R¹ or R² as ethyl, propyl, iso-propyl,tert-butyl and cyclopropyl.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (V) into a compound of formula(IV)

More preferably the intra-molecular cyclisation or compound (V) isinduced by removal of the protecting group R⁵. Preferably, for thisembodiment, R⁵ is benzyloxycarbonyl (Cbz), and the process compriseshydrogenating a compound of formula (V) in the presence of a palladiumcatalyst.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VI) into a compound of formula(V)

In one preferred embodiment, the oxidising agent is mCPBA.

In another preferred embodiment, the oxidising agent is a dioxirane.

The use of dioxiranes as oxidising agents is well documented in theliterature [see (a) Hodgson, D. M. et al, Synlett, 310 (2002); (b) Adam,W. et al, Acc. Chem. Res. 22, 205, (1989); (c) Yang, D. et al, J. Org.Chem., 60, 3887, (1995); (d) Mello, R. et al, J. Org. Chem., 53, 3890,(1988); (e) Curci, R. et al, Pure & Appl. Chem., 67(5), 811 (1995); (f)Emmons, W. D. et al, J. Amer. Chem. Soc. 89, (1955)].

Preferably, the dioxirane is generated in situ by the reaction of KHSO₅with a ketone. However, the oxidation step can also be carried out usingan isolated dioxirane, for example a stock solution of the dioxiraneformed from acetone.

More preferably, the dioxirane is generated in situ using Oxone®, whichis a commercially available oxidising agent containing KHSO₅ as theactive ingredient.

Thus, in one preferred embodiment, the claimed process involves the insitu epoxidation of a compound of formula (VI) using Oxone®(2KHSO₅.KHSO₄.K₂SO₄) and a ketone co-reactant.

As mentioned above, the active ingredient of Oxone® is potassiumperoxymonosulfate, KHSO₅ [CAS-RN 10058-23-8], commonly known aspotassium monopersulfate, which is present as a component of a triplesalt with the formula 2 KHSO₅.KHSO₄.K₂SO₄ [potassium hydrogenperoxymonosulfate sulfate (5:3:2:2), CAS-RN 70693-62-8; commerciallyavailable from DuPont]. The oxidation potential of Oxone® is derivedfrom its peracid chemistry; it is the first neutralization salt ofperoxymonosulfuric acid H₂SO₅ (also known as Caro's acid).K⁺⁻O—S(═O)₂(—OOH)

Potassium Monopersulfate

Under slightly basic conditions (pH 7.5-8.0), persulfate reacts with theketone co-reactant to form a three membered cyclic peroxide (adioxirane) in which both oxygens are bonded to the carbonyl carbon ofthe ketone. The cyclic peroxide so formed then epoxidises the compoundof formula VI by syn specific oxygen transfer to the alkene bond.

Preferably, the ketone is of formula (XIX)

wherein R^(a) and R^(b) are each independently alkyl, aryl, haloalkyl orhaloaryl.

Where R^(a) and/or R^(b) are alkyl, the alkyl group may be a straightchain or branched alkyl group. Preferably, the alkyl group is a C₁₋₂₀alkyl group, more preferably a C₁₋₁₅, more preferably still a C₁₋₁₂alkyl group, more preferably still, a C₁₋₈ or C₁₋₆ alkyl group, morepreferably a C₁₋₄ alkyl group. Particularly preferred alkyl groupsinclude, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl and hexyl.

As used herein, the term “haloalkyl” refers to an alkyl group asdescribed above in which one or more hydrogens are replaced by halo.

Where R^(a) and/or R^(b) are aryl, the aryl group is typically a C₆₋₁₂aromatic group. Preferred examples include phenyl and naphthyl etc.

As used herein, the term “haloaryl” refers to an aryl group as describedabove in which one or more hydrogens are replaced by halo.

By way of example, the reaction of KHSO₅ (Oxone®) with a ketone offormula XVI would form a dioxirane of formula:

wherein R^(a) and R^(b) are as defined above.

More preferably, R^(a) and R^(b) are each independently alkyl orhaloalkyl.

In a highly preferred embodiment, at least one of R^(a) and R^(b) is ahaloalkyl, more preferably, CF₃ or CF₂CF₃.

In one preferred embodiment, R^(a) and R^(b) are each independentlymethyl or trifluoromethyl.

In one preferred embodiment of the invention, the ketone is selectedfrom acetone and a 1,1,1-trifluoroalkyl ketone.

In a more preferred embodiment of the invention, the trifluoroalkylketone is 1,1,1-trifluoroacetone or 1,1,1-trifluoro-2-butanone, morepreferably 1,1,1-trifluoro-2-butanone.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VII) into a compound offormula (VI)

Preferably the process comprises treating a compound of formula (VII)with tosyl chloride in pyridine. Alternatively the process comprisestreating a compound of formula (VII) with tosyl chloride indichloromethane and triethylamine.

In one preferred embodiment the process of the invention comprises thestep of converting a compound of formula (VIII) into a compound offormula (VII)

where W is halogen or tosyl.

Preferably, this step comprises the steps of:

-   (a) reacting a compound of formula (VIII), where W is halogen or    OTs, with aqueous ammonia and alcohol; and-   (b) converting the product formed in step (a) to a compound of    formula (VII).

Preferably, steps (a) and (b) of the above process are a one-potprocess.

In one particularly preferred embodiment, R⁵ is benzyloxycarbonyl, andstep (b) comprises treating the mixture formed in step (a) withbenzyloxycarbonyl chloride.

Preferably, W is I, Br or OTs, more preferably, Br or OTs, even morepreferably OTs.

Preferably, the alcohol is isopropyl alcohol or ethanol.

In one preferred embodiment of the invention, said compound of formulaVIII is prepared from a compound of formula IX

Preferably, the above process comprises treating said compound offormula IX with methyl lithium.

More preferably, compound of formula IX is compound 47 and compound offormula VIII is compound 14; or compound of formula IX is compound 46and compound of formula VIII is compound 13. Treatment ofmonobromotosylates 46 or 47 with zinc dust at room temperature inorganic/aqueous mixtures (most preferably an isopropanol,tetrahydrofuran, water, ammonium chloride mixture) provides alcohols 13and 14 respectively in high yield. Additionally, completion of theone-pot conversion gives alcohols VIIa and VIIb with definedstereochemistry and in high yield.

Commencing from the commercially available sugars isomannide andisosorbide, the present invention also provides facile preparation ofmonobromotosylates 46 and 47 One highly preferred preparation is shownbelow in Scheme 15

Isosorbide (43) is converted to the di-tosylate (42) which is obtainedfollowing recrystallisation from methanol in 97% yield. Mono-brominationis effected by 2.5 eq lithium bromide in DMSO (or DMF) with temperaturecontrol 110° C.→120° C. The product bromide is isolated followingextractive work-up and purification either by column chromatography(74%) or attractive for large scale by recrystallisation from methanolgiving a first crop of 55% plus mother liquors containing good qualitymaterial that may be pooled from batch runs and purified later. Thus,preparation of monobromotosylate (47) with defined stereochemistry bymethods in Scheme 15 is attractive for large scale applications.Treatment of monobromotosylate (47) with zinc dust at room temperaturein organic/aqueous mixtures (most preferably an isopropanol,tetrahydrofuran, water, ammonium chloride mixture) provides alcohol (14)which is derivatised as the Cbz compound (18) through one potconversion.

Treatment of isomannide (40) (Scheme 16) with tosylchloride (2.2 eq) ina bi-phasic potassium hydroxide/dichloromethane/carbon tetrachloridemixture at 0° C. gives ditosylate (39) in 48% yield following simplefiltration and trituration with methanol. Alternatively, treatment ofisomannide (40) with tosylchloride (0.5 eq) in a biphasic potassiumhydroxide/dichloromethane/carbon tetrachloride mixture at 0° C. givesmonotosylate in 38% yield following simple extraction andre-crystallisation from carbon tetrachloride (conditions as described inU.S. Pat. No. 6,858,632). Although the monotosylate can be obtained inhigher yield by treatment of isomannide (40) with tosylchloride inpyridine, purification currently requires column chromatography whichmay becomes undesirable at large scale. Monobromotosylate (46) may thenbe prepared by treatment of ditosylate (39) with lithium bromide in DIME(29% yield following chromatography) or by treatment of monotosylateunder Mitsunobu conditions with carbon tetrabromide (63% yield followingchromatography). Treatment of monobromotosylate (46) with zinc dust atroom temperature in organic/aqueous mixtures (most preferably anisopropanol, tetrahydrofuran, water, ammonium chloride mixture) providesalcohol (13) which is derivatised as the Cbz compound (17) through onepot conversion.

In one highly preferred embodiment of the invention, the6-alkyl-5,5-bicylic core is prepared in accordance with the steps setforth in Scheme 1 below:

The alcohol functionality of (18) may be derivatised as the para-toluenesulphonate (Ts) giving(R)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl4-methylbenzenesulfonate (32b) which proceeds through the anti-epoxide(R)-2-(benzyloxycarbonylamino)-1-((1S,2S,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)ethyl4-methylbenzenesulphonate (33b). Hydrogenation of tosylate (33b)provides free amine that undergoes intramolecular cyclisation to provideintermediate (74). Intermediate (74), either as the free base orhydrochloride salt, undergoes displacement with an excess of a varietyof suitable alkylmetal reagents e.g. a mixture of 2 eq. MeLi to 1 eq.Cu(I) Br that generates Li—Cu(Me)₂ as the active species, to give the6-alkyl analogues with retention of configuration. By analogy a similardisplacement with alternative alkylmetal reagents may be performed togive for example R¹ or R² as ethyl, propyl, iso-propyl, tert-butyl andcyclopropyl. Urethane protection of the secondary amine of the bicyclicintermediate (107) followed by oxidation to ketone provides intermediate(2d) that is particularly useful for solid phase synthesis of compoundsof general formula I.

Advantageously, the epoxidation to give the desired anti-epoxide isdirected by the presence of the tosylate group.

An analogous reaction scheme can be applied to the enantiomer of (18),namely, benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17), proceeding through the analogous anti-epoxide(S)-2-(benzyloxycarbonylamino)-1-((1S,2S,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)ethyl4-methylbenzenesulphonate (32) (Scheme 2).

The tosyl group of bicyclic intermediates (74) and (85) can act as aleaving group that undergoes displacement with an excess of a variety ofsuitable alkylmetal reagents e.g. a mixture of 2 eq. MeLi to 1 eq. Cu(I)Br that generates Li—Cu(Me)₂ as the active species, to give the 6-alkylanalogues with retention of configuration.

Alternatively, intermediate tosylate (74) may be Boc protected to giveprotected analogue (35b) that may undergo inversion to bromide (111)through treatment with LiBr in DMF at typically 130° C. (Scheme 4).Acidolytic removal of Boc provides intermediate bromide (112) thatundergoes displacement with an excess of a variety of suitablealkylmetal reagents e.g. a mixture of 2 eq. MeLi to 1 eq. Cu(I) Br thatgenerates Li—Cu(Me)₂ as the active species, to give the 6-alkylanalogues with retention of configuration. e.g. (109; R¹=Me).

Alternative Preparation of 6-alkyltetrahydrofuro[3,2-b]pyrrol-3-onecores

An alternative synthesis of 6-alkyl substituted bicyclic building blocksmay be achieved through the chemistries described in Schemes 6, 7, 8 and9.

Isomannide (40) is mono tert-butyldixnethylsilyl (TBDMS) protected bytreatment with tert-butyldimethylsilyl chloride and imidazole in DMF togive intermediate (86). Oxidation of alcohol (86) with Dess-Martinperiodinane in DCM provides(3aS,6R,6aS)-6-(tert-butyldimethylsilyloxy)tetrahydrofuro[3,2-b]furan-3(2H)-one (87), an intermediate suitable for reaction with a variety ofWittig reagents. For example, reaction of ketone (87) with potassiumtert-butoxide and methyltriphenylphosphonium bromide in THF providesexocyclic alkene (88) in 91% yield following chromatography.Hydrogenation of alkene (88) over Pd—C provides an ˜9:1 mixture ofmethyl analogues (89a) and (89b) respectively that are not readilyseparated by silica column chromatography. Subsequenttransformations/purifications provide further enrichment of the majorisomer derived from (89a). Removal of TBDMS protection from intermediate(89a) may be performed with TBAF in THF and subsequent treatment ofalcohol (90a) with p-toluenesulphonyl chloride and pyridine in DCM givestosyl intermediate (91a) in high yield.

Then following the general theme detailed previously in Scheme 16,tosylate (91a) may be converted to the monobromide (92) by treatmentwith lithium bromide in DMF. Treatment of bromide (92) with zinc dust inammonium chloride and THF followed by extraction then treatment withtriethylamine and methanesulphonyl chloride provides mesylate (93).Preparation of amine (94) may be achieved by direct treatment ofmesylate (93) with ammonia in propan-2-ol or via the 2-step procedure ofazide displacement of mesylate with sodium azide in DMF followed byreduction of azide to amine (94) through treatment withtriphenylphosphine and water in DMF. Amine (94) may then be Cbzprotected by treatment with Cbz-Cl and sodium carbonate in aqueousdioxan. Epoxidation of alkene (95) through use of 1,1,1-trifluoroacetoneprovides an 3.5:1 mixture of the desired anti-(96) and side-productsyn-(96) respectively. Treatment of epoxide mixture (96) with sodiumhydride in anhydrous THF provides a new slower eluting product on TLCthat is the desired bicycle (3R,3aR,6R,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2a). Hydrogenation, Fmoc protection and oxidation provides intermediateketone (2d; R²=Me) that is particularly suited to solid phase synthesisof analogues of general formula I (R²=Me).

Alternatively, ketone (87) may be treated with triphenylphosphine anddibromodifluoromethane in N,N-dimethylacetamide to givetert-butyl((3R,3aS,6aR)-6-(difluoromethylene)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(97) as detailed in Scheme 8.

Subsequent hydrogenation of alkene (97) over Pd—C provides an ˜9:2mixture of the difluoromethyl analogues (98a) and (98b) respectively,that are readily separated by silica column chromatography. Removal ofTBDMS protection from intermediate (98a) may be performed with TBAF inTHF and subsequent treatment of alcohol (99a) with p-toluenesulphonylchloride and pyridine in DCM gives tosyl intermediate (100a) in highyield. Analogous reactions may be performed on (98b) to give theopposite 6-difluoromethyl isomer (100b).

Then in an analogous manner to that described in Scheme 7, intermediate(100a) may be converted into (3aS,6R,6aR)-(9H-Fluoren-9-yl)methyl6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d; R²═CHF₂) (Scheme 9).

In an analogous manner, intermediate (100b) may be converted into(3aS,6S,6aR)-(9H-Fluoren-9-yl)methyl6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d′; R¹═CHF₂).

Preparation of Novel Aminoacids

The novel aminoacid (S)-2-amino-2-(1-methylcyclopentyl)acetic acid thatforms an intrinsic feature of a selection of compounds of formula I maybe prepared following adaptation of a variety of known generalliterature syntheses of aminoacids. In one such method (Scheme 17),commercially available methyl cyclopentanecarboxylate (127) (CAS4630-80-2) is converted to methyl 2-(1-methylcyclopentyl)acetate (131)as detailed in WO-A-06064286. Ester (131) is readily hydrolysed to2-(1-methylcyclopentyl)acetic acid (132) using LiOH in methanol.Preparation of(S)-4-benzyl-3-(2-(1-methylcyclopentyl)acetyl)oxazolidin-2-one (133) isthen completed using commercially available (S)-4-benzyl-2-oxazolidinone(CAS 90719-32-7) following the general methods detailed in WO98017626(pg 49).

Asymmetric addition of azide is then conducted by deprotonation of thechiral auxiliary (133) and reaction with trisyl azide. Reduction ofazide (134) and concomitant Boc amino protection following the generalmethods detailed in U.S. Pat. No. 5,128,448 provides intermediate (135).Finally, hydrolysis of the auxiliary is conducted with hydrogen peroxideand lithium hydroxide following the general methods detailed in U.S.Pat. No. 5,128,448. The final product(S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopentyl)acetic acid(136) is obtained following simple aqueous extraction (Scheme 18).

Synthesis of Compounds of Formula (I)

To those skilled in the practices of organic chemistry, compounds ofgeneral formula (I) may be readily synthesised by a number of chemicalstrategies, performed either in solution or on the solid phase (seeAtherton, E. and Sheppard, R. C. In ‘Solid Phase Peptide Synthesis: APractical Approach’, Oxford University Press, Oxford, U.K. 1989, for ageneral review of solid phase synthesis principles), or a combinationthereof.

Compounds of general formula (I) may be conveniently considered as acombination of three building blocks (P1, P2 and P3) that respectivelyoccupy the S1, S2 and S3 binding sites of the protease (see Berger, A.and Schechter, I., Philos. Trans. R. Soc. Lond. [Biol.], 257, 249-264,1970 for a description of the designation of enzyme S-subsites andsubstrate P-subsites within enzyme-substrate or enzyme-inhibitorcomplexes). The notional concepts of P1, P2 and P3 are used herein forconvenience only and the above-mentioned compounds are intended to bewithin the scope of the invention regardless of binding mode.

A suitably protected and/or activated building block may then beprepared and subsequently chemically bonded (coupled) together withother building blocks to provide compounds of general formula (I).

Compounds of formula (I) may be prepared: (1) by the stepwise additionof P3 and P2 to the bicyclic 6-alkyltetrahydrofuro[3,2-b]pyrrol-3-onecore; or (2) by reaction of the bicyclic6-alkyltetrahydrofuro[3,2-b]pyrrol-3-one core with a P3-P2 precursormolecule; or (3) by introducing the P3-P2 group prior to formation ofthe bicyclic 6-alkyltetrahydrofuro[3,2-b]pyrrol-3-one core, i.e. priorto the oxidation step or prior to the intramolecular cyclisation step.

Thus, alternative orders of coupling of the building blocks arepossible, for example P2+P1→P2−P1 then addition of P3→P3−P2−P1 orP3+P2→P3−P2 then addition to P1→P3−P2−P1. Within each of thesecombinations each of the P1, P2 or P3 building blocks may containadditional alternative functionalities that are further transformedfollowing coupling to give the final compound. For example the ketonefunctionality of the P1 building block may be protected as a ketalduring coupling of building blocks and transformed to the final ketoneby hydrolysis following completion of the coupling reactions.Alternatively, the ketone functionality of the P1 building block may beinitially introduced via a lower oxidation state such as thecorresponding alcohol and following completion of the coupling reactionsbe re-introduced by oxidation of the alcohol. Alternatively, the ketonefunctionality of the P1 building block may be protected through asemi-carbazone suitable for solid phase synthesis (e.g. see WO 02/057270and references cited therein) and following completion of the couplingreactions released from the solid phase by acidolytic reaction.

The chemical bond formed by coupling of the building blocks is asecondary amide (P3−P2) or a tertiary amide (P2−P1) that are formedthrough reaction of an activated carboxylic acid with a primary andsecondary amine respectively. Many methods are available for activationof a carboxylic acid prior to coupling to an amine and in principle, anyof these methods may be used herein. Typical carboxylic acid activationmethods are exemplified but not restricted to the azide method, mixedanhydride method (e.g. via isobutylchloroformate), carbodiimide methods(e.g. via dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-ethyl-3-(3′-dimethylamino propyl)carbodiimide), active ester method(e.g. via p-nitrophenyl ester, N-hydroxysuccinic imido ester,pentafluorophenyl ester), uronium method (e.g. via addition of HBTU,PyBop, BOP), carbonyldiimidazole method or via pre-formation of acylfluorides or acyl chlorides. In some instances the coupling reaction maybe enhanced by the addition of a further activation catalyst such as1-hydroxybenzotriazole, or 4-dimethylaminopyridine. A generaldescription of carboxylic acid activation techniques and the use ofactivation additives may be found in Bodanszky, M. ‘Principles ofPeptide Synthesis’, 2^(nd) rev. ed., Springer-Verlag, Berlin, 1993 andreferences cited therein.

The α-amino group of the P2 aminoacid building block is usuallyprotected during coupling reactions to the P1 building block to avoidthe formation of undesired self-condensation products. The art ofα-amino protection is well known in peptide chemistry (e.g. seeBodanszky, M. ‘Principles of Peptide Synthesis’, 2^(nd) rev. ed.,Springer-Verlag, Berlin, 1993 and references cited therein) and exampleprotection groups include, but are not limited to,9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc),benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc) andtrichloroethoxycarbonyl (Treoc). The Fmoc group is particularly wellsuited for solid phase syntheses (e.g. see Atherton, E.; Sheppard, R. C.in ‘Solid Phase Peptide Synthesis A Practical Approach’, IRL Press,Oxford, U.K., 1989) typically being removed by treatment with 20% v/vpiperidine in dimethylformamide or 1% v/v1,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide. The Boc groupis particularly well suited to solution phase syntheses typically beingremoved by treatment with trifluoroacetic acid based mixtures or HCl indioxan or ethyl acetate. The Cbz group is also particularly well suitedfor solution phase syntheses typically being removed by catalytichydrogenation with hydrogen and palladium catalysis or by treatment withHBr in acetic acid. Once the coupling sequence is complete, anyprotecting groups are removed in whatever manner is dictated by thechoice of protecting groups (for a general description of protectinggroups and their respective stabilities and methods of removal seeGreene, T. W. and Wuts, P. G. M. ‘Protective Groups in OrganicSynthesis’ John Wiley and Sons, New York, 1991 and references therein).

In the simplest example, the entire left hand portion of a compound ofgeneral formula (I) (i.e. P3−P2) as the carboxylic acid can be preparedin solution by traditional organic chemistry methods and coupled toketone, alcohol or ketal intermediates such as compounds (IIb), (IIc)and (IId). Then oxidation of the alcohol intermediate (e.g. Dess-Martinperiodinane in DCM) or acidolytic cleavage of the ketal intermediateprovides compounds of general formula (I). The alcohol oxidation routeis particularly useful when the compound of general formula (I) containsa substituent that is labile to trifluoroacetic acid, this being thefinal reagent used in each of the solid phase syntheses.

Examples of these different coupling tactics have been detailedpreviously (see (1) Quibell, M. et. al., Bioorg. Med. Chem. 13, 609-625,2005. (ii) Wang, Y. et. al., Bioorg. Med. Chem. Lett. 15, 1327-1331,2005) and the optimum synthetic route is dependant upon the specificsubstituent combinations of the target compound of general formula (I).

In more detail, one preferred strategy for the synthesis of compounds ofgeneral formula (I) comprises:—

-   (a) Preparation of an appropriately functionalised and protected    bicyclic ketone or bicyclic alcohol building block in solution;-   (b) Attachment of the building block (a) to the solid phase through    a linker that is stable to the conditions of synthesis, but readily    labile to cleavage at the end of a synthesis (see James, I. W.,    Tetrahedron, 55 (Report No 489), 4855-4946, 1999, for examples of    the ‘linker’ function as applied to solid phase synthesis);-   (c) Solid phase organic chemistry (see Brown, R. D. J. Chem. Soc.,    Perkin Trans. 1, 19, 3293-3320, 1998), to construct the remainder of    the molecule;-   (d) Compound cleavage from the solid phase into solution; and-   (e) Cleavage work-up and compound analysis.

A second strategy for the synthesis of compounds of general formula (I)comprises:—

-   (a) Preparation of an appropriately functionalised and protected    bicyclic intermediate building block in solution. Preferred    protecting groups for solution phase chemistry are the    9-fluorenylmethoxycarbonyl (Fmoc), Nα-tert-butoxycarbonyl (Boc),    Nα-benzyloxycarbonyl (Cbz) and Nα-allyloxycarbonyl group (Alloc).-   (b) Standard organic chemistry methods for the conversion of    building block obtained in step (a) towards compounds of general    formula (I).

As mentioned above, in one preferred embodiment of the invention,compounds of formula (I) may be prepared using conventional solutionphase chemistry, for example, as described in Quibell, M et al, Bioorg.Med. Chem., 13, 609-625, 2005 (see in particular, Schemes 3 and 4). Thesolution phase strategy is attractive in being able to generate largerquantities of preferred analogues, typically on a multi-gram tomulti-kilogram scale.

In an alternative preferred embodiment of the invention, compounds offormula (I) may be prepared using conventional solid phase chemistry,for example, as described in Quibell M, et al Bioorg. Med. Chem, 12,5689-5710, 2004, see in particular, Scheme 3 and Section 3.2, andreferences cited therein; and Bioorg. Med. Chem, 13, 609-625, 2005, seeScheme 5 and Section 2.2, and references cited therein). The solid phasestrategy is attractive in being able to generate many thousands ofanalogues, typically on a 5-100 mg scale, through established parallelsynthesis methodologies (e.g. see (a) Bastos, M.; Maeji, N. J.; Abeles,R. H. Proc. Natl. Acad. Sci. USA, 92, 6738-6742, 1995).

The synthetic strategy is based on reversible anchorage of the ketonefunctionality via a hydrazide linker bond using general multipintechniques previously described in the art (Watts J. et al, Bioorg. Med.Chem. 12(11), 2903, 2004; Quibell M., et al, Bioorg. Med. Chem.5689-5710, 2004; Grabowksa U. et al, J. Comb. Chem. 2000, 2(5), 475).

Compounds of formula (III; R⁵=Fmoc) may be oxidised to the correspondingketone (e.g. XVI, Scheme 3) and utilised in a solid phase synthesis ofinhibitor molecules (I). The solid phase linkage of an aldehyde orketone, has previously been described by a variety of methods (e.g. see(a) James, I. W., 1999, (b) Lee, A., Huang, L., Ellman, J. A., J. Am.Chem. Soc, 121(43), 9907-9914, 1999, (c) Murphy, A. M., et al, J. Am.Chem. Soc, 114, 3156-3157, 1992). A suitable method amenable to thereversible linkage of an alkyl ketone functionality is through acombination of the previously described chemistries. The semicarbazide,4-[[(hydrazinocarbonyl)amino]methyl]cyclohexane carboxylic acid.trifluoroacetate (Murphy, A. M., et al, J. Am. Chem. Soc, 114,3156-3157, 1992), may be utilised as illustrated in Scheme 3,exemplified by linkage of the Fmoc protected6-alkyltetrahydrofuro[3,2-b]pyrrol-3-one (XVI).

Construct (XVII) is prepared through reaction of the linker molecule andthe 6-alkyltetrahydrofuro[3,2-b]pyrrol-3-one (XVI) by refluxing inaqueous ethanol/sodium acetate. Standard solid phase techniques (e.g.see Atherton, E. and Sheppard, R. C., 1989) are used to anchor theconstruct to an amino-functionalised solid phase through the freecarboxylic acid functionality of (XVII), providing the loaded construct(XVIII). Loaded construct (XVIII) be reacted with a wide range ofcarboxylic acids available commercially or in the literature, tointroduce the left-hand portion ‘P3−P2’.

Preferred carboxylic acids for the introduction of the [R⁹—CO] synthonare known in the literature with the following representative examples;4-(5-(piperidin-1-ylmethyl)thiophen-2-yl)benzoic acid (CAS 860343-90-4),4-(5-(morpholinomethyl)thiophen-2-yl)benzoic acid (CAS 860344-74-7),4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzoic acid (CAS294622-47-2),4-(2-(4-(2-methoxyethyl)piperazin-1-yl)thiazol-4-yl)benzoic acid (CAS860343-99-3), 4-(5-(1-morpholinoethyl)thiophen-2-yl)benzoic acid (CAS860344-01-0), 4-(5-(1-morpholinoethyl)furan-2-yl)benzoic acid (CAS860344-04-3), (S)-4-(2-(1-(dimethylamino)ethyl)thiazol-4-yl)benzoic acid(CAS 860344-10-1),(S)-4-(5-methyl-2-(1-(methylamino)ethyl)thiazol-4-yl)benzoic acid (CAS860344-76-9),(S)-4-(2-(1-(dimethylamino)ethyl)-5-methylthiazol-4-yl)benzoic acid (CAS860344-19-0), (S)-4-(2-(1-(methylamino)ethyl)thiazol-5-yl)benzoic acid(CAS 860344-78-1), (S)-4-(2-(1-(methylamino)ethyl)thiazol-4-yl)benzoicacid (CAS 860344-79-2),4-(2-(4-fluoro-1-methylpyrrolidin-2-yl)thiazol-4-yl)benzoic acid (CAS860344-38-3), 4-(3-methyl-5-(morpholinomethyl)thiophen-2-yl)benzoic acid(CAS 860344-81-6), 3-methyl-4-(5-(morpholinomethyl)furan-2-yl)benzoicacid (CAS 860344-82-7),4-(5-methyl-2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzoic acid (CAS860344-50-9), 4-(2-morpholinothiazol-4-yl)benzoic acid (CAS860344-51-0), 4-(2-(piperidin-1-yl)thiazol-4-yl)benzoic acid (CAS860344-52-1), 4-(2-(dimethylamino)thiazol-4-yl)benzoic acid (CAS849682-29-7), 4-(2-(isopropyl(methyl)amino)-5-methylthiazol-4-yl)benzoicacid (CAS 860344-56-5), 4-(2-(methylamino)thiazol-4-yl)benzoic acid (CAS860344-57-6), 4-(2-(4,4-difluoropiperidin-1-yl)thiazol-4-yl)benzoic acid(CAS 860344-58-7), 4-(2-(isopropylamino)thiazol-4-yl)benzoic acid (CAS860344-59-8), 4-(2-(piperidin-4-yl)thiazol-4-yl)benzoic acid (CAS860344-62-3), 4-(2-(1-methylpiperidin-4-yl)thiazol-4-yl)benzoic acid(CAS 860344-63-4), 4-(2-(pyridin-3-ylamino)thiazol-4-yl)benzoic acid(CAS 294622-46-1), 4-(2-(pyridin-2-ylamino)thiazol-4-yl)benzoic acid(CAS 860344-64-5), 4-(2-(cyclopentylamino)thiazol-4-yl)benzoic acid (CAS860344-65-6), 4-(2-(cyclopropylamino)thiazol-4-yl)benzoic acid (CAS860344-66-7), 4-(2-(cyclopropyl(methyl)amino)thiazol-4-yl)benzoic acid(CAS 860344-67-8), 4-(2-(1-methylpyrrolidin-3-yl)thiazol-4-yl)benzoicacid (CAS 860344-80-5),4-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)benzoic acid (CAS860344-69-0), 4-(6-morpholinopyridin-2-yl)benzoic acid (CAS860344-70-3). Typical preparations for these general types of carboxylicacids are extensively detailed in Palmer, J. T. et al, J. Med. Chem.,2005, 48(24), 7520-34 and WO05066180. General methods for thepreparation of 4-(4-alkylpiperazin-1-yl)benzoic acids and4-(1-alkylylpiperidin-4-yl)benzoic acids are given in WO0158886.

The present invention is further described by way of example.

EXAMPLES General Procedures

Solvents were purchased from ROMIL Ltd, U.K. at SpS or Hi-Dry gradeunless otherwise stated. ¹H NMR and ¹³C NMR were obtained on a BrukerDPX400 (400 MHz ¹H frequency and 100 MHz ¹³C frequency; QXI probe) orBruker Avarice 500 MHz (TXI probe with ATM) in the solvents indicated.Chemical shifts are expressed in parts per million (δ) and arereferenced to residual signals of the solvent. Coupling constants (J)are expressed in Hz. All analytical HPLC were obtained on PhenomenexJupiter C₄, 5μ, 300 Å, 250×4.6 mm, using mixtures of solvent A (0.1% aqtrifluoroacetic acid (TFA)) and solvent B (90% acetonitrile/10% solventA) on automated Agilent systems with 215 and/or 254 nm UV detection.Unless otherwise stated a gradient of 10 to 90% B in A over 25 min at1.5 mL/min was performed for full analytical HPLC. HPLC-MS analysis wasperformed on an Agilent 1100 series LC/MSD, using automated Agilent HPLCsystems, with a gradient of 10 to 90% B in A over 10 min on PhenomenexLuna C₈, 5μ, 300 Å, 50×2.0 mm at 0.6 mL/min. Semi-preparative HPLCpurification was performed on Phenomenex Jupiter C₄, 5μ, 300 Å, 250×10mm, using a gradient of 10 to 90% B in A over 25 min at 4 mL/min onautomated Agilent systems with 215 and/or 254 nm UV detection. Flashcolumn purification was performed on silica gel 60 (Merck 9385) or usingisolute SPE flash silica columns (Biotage, Hengoed, UK).

Preparation of benzyl (S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17) (i) Preparation of(3R,3aS,6R,6aS)-hexahydrofuro[3,2-b]furan-3,6-diylbis(4-methylbenzenesulfonate) (39)

Isomannide (40) (50 g, 342.5 mmol) and p-toluenesulphonyl chloride(143.6 g, 753.2 mmol) were dissolved in a mixture of carbontetrachloride (300 mL), dichloromethane (30 mL) and water (250 mL). Theflask was cooled to 0° C. and a solution of potassium hydroxide (42.0 g,750.0 mmol) in water (42 mL) added dropwise over 2 hours with stirringunder argon. The resulting biphasic mixture was stirred vigorously at 0°C. for 24 hours. The resulting off-white precipitate, comprising amixture of mono- and bistosylates (approximately 1:1), was collected byfiltration in vacuo. The filter cake was washed with water thentriturated with methanol (500 mL). The solid was isolated by filtrationin vacuo to obtain ditosylate (39) as an off-white powder (75 g, 48%).[α]_(D) ¹⁸+96.7° (c=10.5, CHCl₃).

(ii) Preparation of(3R,3aS,6S,6aS)-6-bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (46)

A stirred mixture of ditosylate (39) (16.9 g, 37.22 mmol) and lithiumbromide (4.85 g, 55.84 mmol) in N,N-dimethylformamide (100 mL) washeated at 100° C. for 27 hours. The mixture was allowed to cool thenwater (150 mL) added before extracting with tert-butyl methyl ether(1×100 mL then 5 x′50 mL). The organic phase was dried (MgSO₄), filteredand reduced in vacuo to give a colourless oil which solidified onstanding. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 0:100 to 80:20 gave bromotosylate (46) as awhite solid (2.86 g, 29%). TLC (R_(f)=0.45 diethyl ether:heptane, 1:1),analytical HPLC: R_(f)=16.768 min; HPLC-MS: 363.1/365.0 [M+H]⁺,380.1/382.1, 749.0/751.0 [2M+Na]⁺; [α]_(D) ¹⁸+64.7° (c=8.5, CHCl₃);δ_(H) (500 MHz, CDCl₃) 2.45 (3H, s, CH₃), 3.74 (1H, dd, J=9.60 and 7.05Hz, CH₂), 3.95 (1H, dd, J=9.60 and 6.47 Hz, CH₂), 4.14-4.22 (2H, m,CH₂), 4.29 (1H, d, J=3.03 Hz, CHBr), 4.68 (1H, d, J=4.03 Hz, CHCH), 4.76(1H, t, J=4.48 Hz, CHOTs), 4.87 (1H, m, CHCH), 7.36 (2H, brd, J=7.97 Hz,aromatic CH₃CCH), 7.83 (2H, brd, J=8.33 Hz, aromatic OSO₂CCH). δ_(C)(125 MHz, CDCl₃) 21.69 (CH₃), 50.06 (CHBr), 70.26 (CH₂CHOTs), 76.54(CH₂CHBr), 78.27 (CHOTs), 80.17 and 88.80 (CHCHCHOTs), 127.98 and 129.94(aromatic CH), 133.01 (CHOSO₂C quaternary), 145.28 (CH₃C quaternary).

(iii) Preparation of(3R,3aS,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (50)

Isomannide (40) (10 g, 68.49 mmol) and p-toluenesulphonyl chloride (6.53g, 34.25 mmol) were dissolved in a mixture of carbon tetrachloride (50mL), dichloromethane (5 mL) and water (40 mL). The flask was cooled to0° C. and a solution of potassium hydroxide (1.92 g, 34.25 mmol) inwater (5 mL) added dropwise over 30 minutes with stirring. The resultingbiphasic mixture was stirred at 0° C. for 7 hours. Then off-whiteprecipitate was collected by filtration in vacuo then partitionedbetween dichloromethane (30 mL) and water (10 mL). The organic phase waswashed with brine (2×10 mL) then dried (Na₂SO₄), filtered and reduced invacuo to leave a colourless solid. Recrystallisation from carbontetrachloride gave monotosylate (50) as colourless granules (3.92 g,38%). TLC (R_(f)=0.11, EtOAc:heptane 1:1); analytical HPLC main peak,R_(t)=10.692 min; HPLC-MS 318.2, 323.1 [M+Na]⁺, 623.2 [2M+Na]⁺; [α]_(D)¹⁸ +72.2° (c=5.4, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (3H, s, CH₃), 3.54(1H, dd, J=9.31 and 7.23 Hz, OCH₂CHOH), 3.78 (1H, dd, J=9.18 and 7.59Hz, OCH₂CHOTs), 3.95 (1H, dd, J=9.36 and 6.45 Hz, OCH₂CHOH), 4.01 (1H,dd, J=9.33 and 6.64 Hz, OCH₂CHOTs), 4.26 (1H, m, CHOH), 4.42 and 4.48(each 1H, brt, J=5.03 and 5.00 Hz respectively, CHCHCHOH and CHCHCHOTs),4.90 (1H, dd, J=12.15 and 6.84 Hz, CHOTs), 7.37 (2H, d, J=8.13 Hz,aromatic CH₃CCH), 7.82 (2H, d, J=8.20 Hz, aromatic OSO₂CCH); δ_(C) (125MHz, CDCl₃) 21.69 (CH₃), 70.03 (CH₂CHOTs), 72.29 (CHOTs), 74.02(CH₂CHOH), 80.00 (CH₂CHOH), 81.36 (CHCHOTs), 81.76 (CHCHOH), 128.00 and129.89 (aromatic CH), 133.04 (CHOSO₂C quaternary), 145.26 (CH₃Cquaternary).

(iv) Alternative preparation of(3R,3aS,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (50)

A solution of p-toluenesulfonyl chloride (24.8 g, 130 mmol) in pyridine(150 mL) was added to a stirred solution of isomannide (40) (19.0 g, 130mmol) in pyridine (150 mL) over 1 hour at 0° C. then stirred at ambienttemperature for 1 hour. The mixture was poured onto iced-water (1 L)then extracted with dichloromethane (3×300 mL). The organic phase washedwith brine (300 mL), dried (MgSO₄), filtered and reduced in vacuo toleave a residue. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 0:100 to 50:50 gave monotosylate (50) (23.4 g,60%) as a white solid.

(v) Alternative preparation of(3R,3aS,6S,6aS)-6-bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (46)

A solution of carbon tetrabromide (18.12 g, 54.63 mmol) in pyridine (100mL) was added to a solution of monotosylate (50) (14.9 g, 49.66 mmol)and triphenylphosphine (26.1 g, 99.32 mmol) in pyridine (150 mL) over 30minutes, then the mixture heated at 65° C. for 1.5 hours under anatmosphere of argon. Water (200 mL) was added then the aqueous phaseextracted with dichloromethane (5×100 mL). The organic phase was washedwith brine (50 mL), then dried (MgSO₄), filtered and reduced in vacuo toleave a residue which was azeotroped with toluene (5×50 mL). Flashchromatography over silica, eluting with diethyl ether:heptane mixtures0:100 to 100:0 gave bromotosylate (46) (7.70 g, 43%) as a white solid.[α]_(D) ¹⁷ +68.6° (c=0.51, CHCl₃).

(vi) Preparation of (R)-1-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl4-methyl benzenesulfonate (13)

A solution of ammonium chloride (100 mg, 1.87 mmol) in water (1.25 mL)then zinc dust (100 mg, 1.54 mmol) were added to a solution ofbromotosylate (46) (0.5 g, 1.38 mmol) in tetrahydrofuran (5 mL) andpropan-2-ol (2.5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with diethyl ether (20 mL). Hydrochloric acid (1M, 20 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (20 mL) then the combined organicphase was washed with brine (20 mL), then dried (MgSO₄), filtered andreduced in vacuo to leave a residue. Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 20:80 to 50:50 gave alcohol(13) (292 mg, 75%) as a white solid. [α]_(D) ¹⁵ −64.8° (c=9.8, CHCl₃).

(vii) Preparation of benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (17)

Zinc and ‘One-Pot’ Procedure

A solution of ammonium chloride (560 mg, 10.5 mmol) in water (7 mL) wasadded to a solution of bromotosylate (46) (2.86 g, 7.88 mmol) inpropan-2-ol (14 mL) under argon. Zinc dust (560 mg, 8.67 mmol) was thenadded in portions over 4 minutes then the suspension stirred for 16hours before filtering through celite in vacuo. The filter cake waswashed with diethyl ether (60 mL). Hydrochloric acid (1M, 60 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (60 mL) then the combined organicphase was washed with brine (60 mL), then dried (MgSO₄), filtered andreduced in vacuo. The residue was dissolved in ammonium hydroxide (18mL) and a solution of ammonia in propan-2-ol (12 mL, 2.0M, 24 mmol) thendivided into three equal portions and heated in sealed tubes at 75° C.for 16 hours. The mixtures were combined using methanol then thesolvents were removed in vacuo. The residue was azeotroped with diethylether (3×10 mL) to obtain(S)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used withoutfurther purification.

A solution of sodium carbonate (1.75 g, 16.6 mmol) in water (16 mL) wasadded whilst stirring to a solution of(S)-2-amino-1-((S)-2,5-dihydrothran-2-yl)ethanol (assumed to be 7.88mmol) in 1,4-dioxan (20 mL). The mixture was cooled to 0° C. thenbenzylchloroformate (1.69 mL, 11.82 mmol) was added dropwise over 10minutes. The mixture was stirred at 0° C. for 85 minutes, thendichloromethane (75 mL) and water (100 mL) added. The organic phase wasseparated and the aqueous extracted with dichloromethane (2×50 mL). Theorganic layer was washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a residue (3.1 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures20:80 to 70:30 gave alcohol (17) (1.10 g, 53%). [α]_(D) ¹⁸ −83.1°(c=9.9, CHCl₃).

Preparation of Benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18) (i) Preparation of(3R,3aS,6S,6aS)-hexahydrofuro[3,2-b]furan-3,6-diylbis(4-methylbenzenesulfonate) (42)

A stirred solution of p-toluenesulfonyl chloride (57.4 g, 301 mmol) andisosorbide (43) (20 g, 137 mmol) in pyridine (315 mL) was heated at 95°C. for 4.5 hours under an atmosphere of argon then stood at ambienttemperature for 16 hours before being poured onto iced-water (1 L). Theaqueous was extracted with dichloromethane (2×500 mL), then the combinedorganic layers were washed with water (2×500 mL), then dried (Na₂SO₄),filtered then reduced in vacuo to leave a viscous oil (65.22 g). The oilwas crystallized from hot methanol (350 mL). The white solid wascollected by filtration in vacuo, then washed with methanol (100 mL) anddried in vacuo to obtain ditosylate (42) as a white solid (45.87 g,74%). TLC (R_(f)=0.30, EtOAc:heptane 2:3), analytical HPLC single mainpeak, R_(t)=20.219 min., HPLC-MS 455.1 [M+H]⁺, 931.2 [2M+Na]⁺, [α]_(D)²⁰+57.2° (c=10.2, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (6H, s, CH₃), 3.68(1H, dd, J=9.80 and 6.46 Hz, CH₂), 3.82-3.87 (2H, m, CH₂), 3.94 (1H, d,J=11.28 Hz, CH₂), 4.46 (1H, d, J=4.44 Hz, CHCHOTs), 4.58 (1H, t, J₇ 4.74Hz, CHCHOTs), 4.82-4.86 (2H, m, CHOTs), 7.32-7.36 (4H, m, aromaticCH₃CCH), 7.74-7.80 (4H, m, aromatic OSO₂CCH).

(ii) Alternative preparation of(3R,3aS,6S,6aS)-hexahydrofuro[3,2-b]furan-3,6-diylbis(4-methylbenzenesulfonate) (42)

Triethylamine (123.2 mL, 876 mmol) was added dropwise to a stirredsolution of p-toluenesulfonyl chloride (156.6 g, 822 mmol) andisosorbide (43) (40 g, 274 mmol) in dichloromethane (600 mL) over 15minutes. The mixture was stirred at 25° C. for 16 hours then at 50° C.for 4 hours before diluting with dichloromethane (1 L). The organiclayer was washed with water (2×1 L), then dried (Na₂SO₄), filtered thenreduced in vacuo to leave a viscous oil. The oil was crystallized fromhot methanol (600 mL) to obtain ditosylate (42) as a white solid (120.1g, 97%). [α]_(D) ¹⁵+56.3° (c=11.2, CHCl₃).

(iii) Preparation of(3S,3aS,6S,6aS)-6-bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (47)

Lithium bromide (9.6 g, 110.1 mmol) was added to a stirred solution ofditosylate (42) (20.0 g, 44.05 mmol) in dimethylformamide (100 mL) underan atmosphere of argon. The mixture was heated at 110° C. for 5 hoursthen stood at ambient temperature for 3 days, then heated at 90° C. for3.5 hours. The mixture was diluted with water (250 mL) extracted withtert-butyl methyl ether (4×125 mL) then the organic phase washed withwater (3×125 mL), brine (125 mL), dried (MgSO₄), filtered and reduced invacuo to leave a brown oil (16.8 g). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 0:100 to 30:70 gavebromotosylate (47) (11.88 g, 74%) as a pale yellow solid. TLC(R_(f)=0.20, EtOAc:heptane 1:3); analytical HPLC main peak, R_(t)=18.050min; HPLC-MS 381.0/383.0 [M+H₂O+H]⁺, 385.0/387.0 [M+Na]⁺; [α]_(D)¹⁸+51.0° (c 5.0, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.45 (3H, s, CH₃), 3.84(1H, dd, J=11.19 and 3.51 Hz, CH₂), 4.05-4.15 (3H, m, CH₂), 4.28 (1H, d,J=3.40 Hz, CHBr), 4.78 (1H, d, J=3.37 Hz, CHCH), 4.84 (1H, d, J=3.42 Hz,CHOTs), 4.90 (1H, d, J=3.37 Hz, CHCH), 7.36 (2H, brd, J=7.98 Hz,aromatic CH₃CCH), 7.79 (2H, brd, J=8.32 Hz, aromatic OSO₂CCH).

(iv) Alternative preparation of(3S,3aS,6S,6aS)-6-bromohexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (47)

Lithium bromide (19.2 g, 220.2 mmol) was added to a stirred solution ofditosylate (42) (40.0 g, 88.1 mmol) in dimethyl sulfoxide (200 mL) underan atmosphere of argon. The mixture was heated at 110° C. for 8 hoursthen at 120° C. for 1.75 hours. The mixture was diluted with water (500mL) then extracted with tert-butyl methyl ether (4×250 mL). The organicphase was washed with water (3×250 mL) then brine (250 mL), dried(MgSO₄), filtered and reduced in vacuo to leave an orange solid.Recrystallisation from methanol (100 mL) gave bromotosylate (47) (17.47g, 55%) as a pale yellow solid. [α]_(D) ¹⁵+49.5° (c=11.7, CHCl₃).

(v) Preparation of (S)-1-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl4-methyl benzenesulfonate (14)

Ammonium chloride (20 mg, 0.37 mmol) then zinc dust (20 mg, 0.31 mmol)were added to a solution of bromotosylate (47) (100 mg, 0.28 mmol) inethanol (1.5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with ethanol (20 mL) then the filtrate reduced in vacuo toleave a residue (111 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 20:80 to 40:60 gave alcohol (14) (53 mg,68%) as a white solid. TLC (R_(f)=0.15, EtOAc:heptane 1:2); analyticalHPLC main peak, R_(t)=12.543 min; HPLC-MS 285.1 [M+H]⁺, 302.1, 591.2[2M+Na]⁺; [α]_(D) ¹⁵ −86.8° (c=5.3, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.12(1H, brs, OH), 2.44 (3H, s, aryl-CH₃), 3.77 (2H, d, J=4.85 Hz, CH₂OH),4.54-4.58 (3H, m, CH₂OCH), 4.94-4.98 (1H, m, CHOTs), 5.64-5.67 and5.97-6.00 (2H total, m, CH₂CH═CH), 7.33 (2H, brd, J=8.23 Hz, aromaticCH₃CCH), 7.79 (2H, brd, J=8.31 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz,CDCl₃) 21.660 (CH₃), 62.303 (CH₂OH), 75.940 (OCH₂CH═CH), 82.720 and85.221 (OCHCHOTs), 124.792, 127.977, 129.479 and 129.749 (OCH₂CH═CH andaromatic CH), 133.496 (CHOSO₂C quaternary), 144.973 (CH₃C quaternary).

(vi) Alternative preparation of(S)-1-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate (14)

A solution of ammonium chloride (200 mg, 3.7 mmol) in water (2.5 mL)then zinc dust (200 mg, 3.1 mmol) were added to a solution ofbromotosylate (47) (1 g, 235 mmol) in tetrahydrofuran (10 mL) andpropan-2-ol (5 mL) under argon. The mixture was stirred for 16 hoursbefore filtering the suspension through celite in vacuo. The filter cakewas washed with diethyl ether (20 mL). Hydrochloric acid (1M, 20 mL) wasadded to the filtrate then the organic phase separated. The aqueouslayer was extracted with diethyl ether (20 mL) then the combined organicphase was washed with brine (20 mL), then dried (MgSO₄), filtered andreduced in vacuo to leave a residue (1.06 g). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 20:80 to 50:50 gavealcohol (14) (528 mg, 68%) as a white solid. [α]_(D) ¹⁶ −82.7° (c=11.3,CHCl₃).

(vii) Preparation of benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-2-hydroxyethylcarbamate (18)

Zinc and ‘One-Pot’ Procedure.

A solution of ammonium chloride (600 mg, 11.2 mmol) in water (7.5 mL)was added to a solution of bromotosylate (47) (3.0 g, 8.26 mmol) inpropan-2-ol (15 mL) under argon. Zinc dust (600 mg, 9.2 mmol) was thenadded in portions over 4 minutes and the mixture was stirred for 16hours before filtering the suspension through celite in vacuo. Thefilter cake was washed with diethyl ether (60 mL). Hydrochloric acid(1M, 60 mL) was added to the filtrate then the organic phase separated.The aqueous layer was extracted with diethyl ether (60 mL) then thecombined organic phase was washed with brine (60 mL), then dried(MgSO₄), filtered and reduced in vacuo. The residue was dissolved inammonium hydroxide (18 mL) and a solution of ammonia in propan-2-ol (12mL, 2.0M, 24 mmol), then divided into two equal portions and heated insealed tubes at 75° C. for 16 hours. The mixtures were combined usingmethanol then the solvents were removed in vacuo. The residue wasazeotroped with diethyl ether (3×10 mL) to obtain(R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol which was used withoutfurther purification.

A solution of sodium carbonate (1.84 g, 17.4 mmol) in water (16 mL) wasadded whilst stirring to a suspension of(R)-2-amino-1-((S)-2,5-dihydrofuran-2-yl)ethanol (assumed to be 826mmol) in 1,4-dioxan (20 mL). The mixture was cooled to 0° C. thenbenzylchloroformate (1.77 mL, 12.4 mmol) was added dropwise over 5minutes. The mixture was stirred at 0° C. for 55 minutes thendichloromethane (75 mL) and water (100 mL) added. The organic phase wasseparated and the aqueous extracted with dichloromethane (2×50 mL). Theorganic phase was washed with brine (50 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a residue (3.7 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures20:80 to 70:30 gave alcohol (18) (1.26 g, 58%). [α]_(D) ¹⁶ −62.0°(c=5.0, CHCl₃).

Preparation of(S)-2-(Benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl4-methylbenzenesulfonate (32)

A solution of p-toluenesulfonyl chloride (252 mg, 1.32 mmol) in pyridine(7.0 mL), alcohol (17) (290 mg, 1.10 mmol) was stirred at 24° C. for 2days then diluted with water (15 mL). The product was extracted intotert-butyl methyl ether (3×20 mL) then dried (MgSO₄), filtered andreduced in vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 7:93 to 20:80 gave tosylate (32) (282 mg, 61%)as a colourless oil. TLC (R_(f)=0.35, EtOAc:heptane 1:1), analyticalHPLC single main peak, R_(t)=19.02 min., HPLC-MS 418.2 [M+H]⁺, 857.3[2M+Na]⁺; [α]_(D) ¹¹ −86.1° (c=1.103, CHCl₃; δ_(H) (500 MHz, CDCl₃) 2.37(3H, s, aryl-CH₃), 3.29-3.37 and 3.50-3.56 (2H total, m, CH₂NH),4.53-4.56 (2H total, m, OCH₂CH═CH), 4.62-4.66 m, OCHCH═CH), 4.85-4.90(1H, m, CHOTs), 5.02-5.08 (2H, m, OCH₂Ph), 5.02 (1H, brs, NH), 5.65-5.70and 5.94-5.98 (2H total, m, CH₂CH═CH), 7.27 (2H, d, J=8.12 Hz, aromaticCH₃CCH), 7.29-7.37 (5H, m, phenyl CH), 7.76 (2H, d, J=8.23 Hz, aromaticOSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.609 (aryl-CH₃), 41.749 (CH₂NHCbz),66.833 (CH₂Ph), 75.939 (OCH₂CH═CH), 81.235 (CHOTs), 85.203 (OCHCH═CH),124.702, 127.887, 128.026, 128.128, 128.504, 129.687 and 129.757(OCH₂CH═CH and aromatic CH), 133.591 (CHOSO₂C quaternary), 136.368 (Cbzquaternary), 144.906 (CH₃C quaternary), 156.271 (Cbz C═O).

Alternative Preparation of(S)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydro furan-2-yl)ethyl4-methylbenzenesulfonate (32)

A solution of p-toluenesulfonyl chloride (760 mg, 3.99 mmol) in pyridine(10.0 mL), alcohol (17) (600 mg, 2.28 mmol) was stirred at 40° C. for atotal of 6 hours and stood at 24° C. for 16 hours then diluted withwater (20 mL). The product was extracted into tert-butyl methyl ether(2×50 mL) then dried (MgSO₄), filtered and reduced in vacuo. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures10:90 to 30:70 gave tosylate (32) (789 mg, 83%) as a white solid.

Preparation of(R)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl4-methyl benzenesulfonate (32b)

A solution of p-toluenesulfonyl chloride (368 mg, 2.03 mmol) in pyridine(1.5 mL) was added to alcohol (18) (333 mg, 1.27 mmol). The mixture wasstirred at 14° C. for 16 hours and at 24° C. for 3.5 hours then dilutedwith tert-butyl methyl ether (35 mL). The organic layer was washed withwater (15 mL), brine (15 mL), then dried (MgSO₄), filtered and reducedin vacuo to leave a pale yellow oil (0.712 g). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 15:85 to 30:70 gavetosylate (32b) (429 mg, 81%) as a white solid. TLC (R_(f)=0.75,EtOAc:heptane 3:1), analytical HPLC single main peak, R_(t)=18.93 min.,HPLC-MS 374.2, 418.2 [M+H]⁺, 857.3 [2M+Na]⁺; [α]_(D) ^(18.5) −30.2°(c=1.326, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.39 (3H, s, aryl-CH₃),3.29-3.37 and 3.53-3.62 (2H total, m, CH₂NH), 4.44-4.50 and 4.52-4.57(2H total, m, OCH₂CH═CH), 4.59-4.65 (1H, m, OCHCH═CH), 4.87-4.92 (1H, m,CHOTs), 5.05 (2H, m, OCH₂Ph), 5.03 (1H, brs, NH), 5.69-5.73 and5.94-5.98 (2H total, m, CH₂CH═CH), 7.28 (2H, d, J=8.10 Hz, aromaticCH₃CCH), 7.29-7.37 (5H, phenyl CH), 7.77 (2H, d, J=8.10 Hz, aromaticOSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.627 (aryl-CH₃), 41.119 (CH₂NHCbz),66.856 (CH₂Ph), 75.987 (OCH₂CH═CH), 82.352 (CHOTs), 85.622 (OCHCH═CH),124.792, 127.825, 128.027, 128.126, 128.504, 129.357 and 129.537(OCH₂CH═CH and aromatic CH), 133.674 (CHOSO₂C quaternary), 136.348 (Cbzquaternary), 144.941 (CH₃C quaternary), 156.273 (Cbz C═O).

Epoxidation studies with(R)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydro furan-2-yl)ethyl4-methylbenzenesnlfonate (32b)

(a) 3-Chloroperbenzoic acid (97 mg, ≦77%, 0.43 mmol) was added to astirred solution of alkene (32b) (36 mg, 0.086 mmol) in dichloromethane(1.5 mL). The mixture was stirred for 20 hours at ambient temperaturethen 3-chloroperbenzoic acid (97 mg, ≦77%, 0.43 mmol) was added andstirring continued for 1 day at 24° C. then diluted with dichloromethane(15 mL). The organic phase was washed with aqueous sodium hydroxidesolution (5%, 10 mL), water (10 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave a residue (0.038 mg). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50gave (in order of elution) anti-(33b) (16 mg, 43%) as a colourlessviscous oil and syn-epoxide (9 mg, 24%) as a white solid. Data foranti-(33b); TLC (R_(f)=0.50, EtOAc:heptane 1:1), analytical HPLC singlemain peak, R_(t)=17.999 min., HPLC-MS 434.1 [M+H]⁺, 456.1 [M+Na]⁺, 889.2[2M+Na]⁺; [α]_(D) ¹⁷ +25.6° (c=2.54, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.41(3H, s, aryl-CH₃), 3.31-3.38 and 3.60-3.66 (2H total, m, CH₂NH), 3.67(1H, d, J=10.46 Hz, OCH₂CH), 3.75 and 3.81 (each 1H, d, J=2.50 and 2.75Hz respectively, OCH₂CHCH), 3.94 (1H, d, J=10.57 Hz, OCH₂CH), 4.07 (1H,d, J=6.90 Hz, OCHCHOTs), 4.60-4.64 (1H, m, CHOTs), 4.97-5.01 (1H brt,NH), 5.08 (2H, brs, CH₂Ph), 7.29-7.37 (7H, aromatic CH₃CCH and phenylCH), 7.78 (2H, d, J=8.18 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃)21.665 (aryl-CH₃), 42.054 (CH₂NHCbz), 56.175 and 57.048 (OCH₂CHCH),67.031 (CH₂Ph), 67.672 (OCH₂CH), 76.732 (OCHCHOTs), 79.388 (CHOTs),127.776, 128.108, 128.222, 128.544 and 130.043 (aromatic CH), 133.249(CHOSO₂C quaternary), 136.192 (Cbz quaternary), 145.487 (CH₃Cquaternary), 156.224 (Cbz C═O).

(b) To a solution of alkene (32b) (262 mg, 0.63 mmol) in acetonitrile (4mL) and aqueous Na₂.EDTA (4 mL, 0.4 mmol solution) at 0° C. was added1,1,1-trifluoroacetone (0.67 mL, 7.54 mmol) via a pre-cooled syringe. Tothis solution was added in portions a mixture of sodium bicarbonate(0.44 g, 5.28 mmol) and OXONE® (1.20 g, 1.95 mmol) over a period of 55minutes. The mixture was stirred for 2.5 hours then diluted with water(25 mL) and the product extracted into dichloromethane (2×25 mL). Thecombined organic layers were washed with brine (12.5 mL) then dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue (310 mg).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 15:85 to 50:50 gave anti-(33b) as a viscous white oil (216 mg,79%).

Epoxidation of (S)-2-(benzyloxycarbonylamino)-1-((S)-2,5-dihydrofuran-2-yl)ethyl 4-methylbenzenesulfonate (32)

(a) To a solution of alkene (32) (765 mg, 1.83 mmol) in acetonitrile (10mL) and aqueous Na₂.EDTA (10 mL, 0.4 mmol solution) at 0° C. was added1,1,1-trifluoroacetone (1.98 mL, 22.0 mmol). To this solution was addedin portions a mixture of sodium bicarbonate (1.29 g, 15.4 mmol) andOXONE® (3.49 g, 5.68 mmol) over a period of 1.5 hours. The mixture wasstirred for 1.5 hours then diluted with water (30 mL) and the productextracted into dichloromethane (3×30 mL). The combined organic layerswere washed with brine (50 mL) then dried (MgSO₄), filtered and reducedin vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 30:70 gave (in order of elution)anti-(33) as a white solid (597 mg, 75%) and syn-epoxide (35 mg, 4%) asa white solid. Data for anti-(33); TLC (R_(f)=0.50, EtOAc:heptane 1:1),analytical HPLC single main peak, R_(t)=17.989 min., HPLC-MS 434.2[M+H]⁺, 889.3 [2M+Na]⁺; [α]_(D) ^(11.5) −49.08° (c=1.630, CHCl₃); δ_(H)(500 MHz, CDCl₃) 2.38 (3H, s, aryl-CH₃), 3.30-3.37 and 3.44-3.50 (2H, m,CH₂NH), 3.73 and 2.74 (2H, each d, J=2.78 and 2.73 Hz respectively,OCH₂CHCH), 3.81 (1H, d, J=10.08 Hz, OCH₂CH), 3.91 (1H, d, J=10.12 Hz,OCH₂CH), 4.13 (1H, d, J=2.04 Hz, OCHCHOTs), 4.83-4.86 (1H, m, CHOTs),4.89-5.00 (1H brt, J=5.39 Hz, NH), 5.02-5.09 (2H, m, CH₂Ph), 7.28 (2H,d, J=8.10 Hz, aromatic CH₃CCH), 7.31-7.38 (5H, phenyl CH), 7.76 (2H, d,J=8.22 Hz, aromatic OSO₂CCH; δ_(C) (125 MHz, CDCl₃) 21.636 (aryl-CH₃),42.085 (CH₂NHCbz), 56.414 and 57.217 (OCH₂CHCH), 66.977 (CH₂Ph), 68.582(OCH₂CH), 76.846 (OCHCHOTs), 79.979 (CHOTs), 127.668, 128.073, 128.241,128.551 and 130.001 (aromatic CH), 133.489 (CHOSO₂C quaternary), 136.172(Cbz quaternary), 145.322 (CH₃C quaternary), 156.247 (Cbz C═O).

Preparation of(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (74)

Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (20 mg) and anti-(33b) (100 mg, 0.25 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred for 4.5 hours before filtering the mixture through celite invacuo. The filter cake was washed with ethanol (10 mL) then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withtoluene (2×3 mL) to obtain(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (74) which was used without furtherpurification.

Preparation of (3R,3aR,6R,6aS)— tert-butyl3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(35b)

A solution of sodium carbonate (56 mg, 0.275 mmol) in water (0.75 mL)was added whilst stirring to a solution of(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (74) in 1,4-dioxan (0.75 mL). A solution ofdi-tert-butyl dicarbonate (60 mg, 0.275 mmol) in 1,4-dioxan (0.5 mL) wasadded dropwise over 5 minutes then the mixture stirred for 1 hour beforeadding an additional aliquot of di-tert-butyl dicarbonate (40 mg, 0.184mmol) in 1,4-dioxan (0.25 mL) dropwise over 1 minute. The mixture wasstirred for 70 minutes then water (5 mL) was added and the productextracted into dichloromethane (3×5 mL). The organic layer was washedwith brine (5 mL), then dried (Na₂SO₄), filtered and reduced in vacuo toleave a residue (132 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 15:85 to 45:55 gave bicyclic alcohol(35b) (58.9 mg, 60%) as a white solid. TLC (R_(f)=0.30, EtOAc:heptane1:1), analytical HPLC single main peak, R_(t)=16.54 min., HPLC-MS 344.1[M+2H−^(t)Bu]⁺, 821.3 [2M+Na]⁺; [α]_(D) ^(18.5) −30.3° (c=6.10, CHCl₃);δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 2:1; 1.44 (6H,brs, (CH₃)₃C, major), 1.46 (3H, brs, (CH₃)₃C, minor), 1.98 (0.33H, d,J=4.00 Hz, OH minor), 2.44 (3H, s, aryl-CH₃), 2.69 (0.66H, d, J=2.88 Hz,OH major), 3.08-3.15 (0.33H, m, BocNCH₂ minor), 3.26-3.32 (0.66H, m,BocNCH₂ major), 3.75-3.87 (2H, m, 1×OCH₂CHOH and 1×BocNCH₂), 3.94-4.02(1H, m, OCH₂CHOH), 4.07 (1H, brs, BocNCH), 4.35 (0.33H, brs, OCH₂CHOHminor), 4.41 (0.66H, brs, OCH₂CHOH major), 4.52 (0.66H, t, J=4.75 Hz,TsOCHCH major), 4.65 (0.33H, t, J=3.95 Hz, TsOCHCH minor), 4.72-4.78(1H, m, TsOCHCH), 7.34 (2H, brd, J=7.82 Hz, aromatic CH₃CCH), 7.82 (2H,brd, J=8.01 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.681(aryl-CH₃), 28.294/28.386 ((CH₃)₃C), 46.810/48.177 (BocNCH₂),68.153/68.484 (BocNCH), 75.484/75.697 (OCH₂CHOH), 76.228/76.980(OCH₂CHOH), 76.269/76.585 (TsOCHCH), 79.391/80.233 (TsOCHCH),81.079/81.139 ((CH₃)₃C quaternary), 127.973, 129.911, 129.966 and130.125 (aromatic CH), 133.144 (CHOSO₂C quaternary), 145.247 (CH₃Cquaternary), 153.161/154.244 (Boc C═O).

Preparation of(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate. hydrochloride (74)

Boc alcohol (35b) (11.0 g, 27.6 mmol) was dissolved in 4N HCl in dioxan(100 mL, 400 mmol) and the mixture stirred at ambient temperature for 1hour. The mixture was then concentrated in vacuo and azeotroped threetimes from toluene to give a pale brown solid (Yield 9.25 g). HPLC-MS3001 [M+H]⁺; δ_(H) (500 MHz, d₆-DMSO) 2.44 (3H, s, CH₃-aryl), 3.13 (1H,dd, J=7.8 Hz, NHCH₂), 3.38 (1H, dd, J=6.7 Hz, NHCH₂), 3.68 (1H, dd,J=2.0, 9.9 Hz, CHOCH₂), 3.93 (1H, d, J=5.3 Hz, NHCHCH), 3.98 (1H, dd,J=4.3, 9.9 Hz, CHOCH₂), 4.50 (1H, m, NHCHCH), 4.57 (1H, t, J=4.9 Hz,TsOCHCH), 5.03 (1H, in, TsOCHCH), 5.71 (1H, b, NH), 7.52 (2H, d, J=8.0Hz, aryl), 7.84 (2H, d, J=8.0 Hz, aryl), 9.92 (2H, b, OH+HCl); δ_(C)(125 MHz, d₆-DMSO) 21.25 (aryl-CH₃), 45.99 (NHCH₂), 67.60 (NHCH), 72.63(OCH₂CHOH), 75.94 (OCH₂CHOH), 77.18 (TsOCHCH), 79.15 (TsOCHCH), 127.84and 130.40 (aromatic CH), 132.28 (CHOSO₂C quaternary), 145.65 (CH₃Cquaternary).

Preparation of (3R,3aR,6R,6aR)-Benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H-carboxylate(108)

A solution of methyllithium (1.6M in diethyl ether, 74.4 mL, 119 mmol)was added dropwise over 13 minutes to a stirred suspension of copper(I)bromide (8.55 g, 59.6 mmol) in tetrahydrofuran (75 mL) at 0° C. Themixture was stirred for 20 minutes then(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-ylmethylbenzenesulfonate hydrochloride (74) (5.0 g, 14.9 mmol) was addedin portions over 8 minutes. The mixture was stirred for 30 minutes at 0°C. then at ambient temperature for 2.5 hours. A solution of sodiumcarbonate (4 g, 37.7 mmol) in water (60 mL) was added dropwise over 10minutes. The mixture was stirred for 15 minutes then benzylchloroformate (4.75 mL, 33.3 mmol) was added over 5 minutes. The mixturewas stirred for 1.75 hours then water (500 mL) was added and the mixtureextracted with dichloromethane (3×250 mL). The combined organic layerswere washed with brine (250 mL), dried (Na₂SO₄), filtered and reduced invacuo to leave a brown oil (6.22 g). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 10:90 to 60:40 gave(3R,3aR,6R,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(108) (2.57 g, 62%) as a brown oil. TLC (R_(f)=0.40, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=10.87 min., HPLC-MS 278.1[M+H]⁺, 300.1 [M+Na]⁺, 577.2 [2M+Na]⁺;

Preparation (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (85)

Ethanol (20 mL) was added dropwise to a mixture of 10% palladium oncharcoal (50 mg) and anti-(33) (578 mg, 1.33 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred for 1.5 hours before filtering the mixture through celite invacuo. The filter cake was washed with ethanol then the solvents removedin vacuo from the filtrate to obtain(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate (85) which was used without furtherpurification.

Preparation of (3R,3aR,6S,6aR)-Benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(110)

A solution of methyllithium (1.6M in diethyl ether, 1.7 mL, 2.68 mmol)was added dropwise over 1 minute to a stirred suspension of copper(I)bromide (192 mg, 1.34 mmol) in tetrahydrofuran (1.7 mL) at 0° C. Themixture was stirred for 20 minutes then a solution of(3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-ylmethylbenzenesulfonate (85) (100 mg, 0.33 mmol) in tetrahydrofuran (2.0mL) was added via cannula. The mixture was stirred for 1 hour at 0° C.then at ambient temperature for 70 minutes. A solution of sodiumcarbonate (89 mg, 0.84 mmol) in water (1.5 mL) was added dropwise over 2minutes. The mixture was stirred for 10 minutes then benzylchloroformate (0.105 mL, 0.74 mmol) was added. The mixture stirred for70 minutes then water (15 mL) was added and the mixture extracted withdichloromethane (10 mL). The aqueous layer was reextracted withdichloromethane (2×5 mL) then the combined organic layers were washedwith brine (5 mL), dried (Na₂SO₄), filtered and reduced in vacuo toleave a pale yellow oil (140 mg). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 10:90 to 45:55 gave(3R,3aR,6S,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(110) (66 mg, 73%) as a colourless oil. TLC (R_(f)=0.30, EtOAc:heptane2:1), analytical HPLC main peak, R_(t)=9.890 min., HPLC-MS 278.1 [M+H]⁺,577.2 [2M+Na]⁺.

Preparation of (3R,3aR,6S,6aR)-(9H-fluoren-9-yl)methyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′; R¹=Me)

Methanol (2.0 mL) was added dropwise to a mixture of 10% palladium oncharcoal (20 mg) and bicyclic alcohol (110) (45 mg, 0.162 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1 hour then filtered through celite in vacuo.The filter cake was washed with ethanol (10 mL) then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withdiethyl ether (3×3 mL) to obtain the crude(3R,3aR,6S,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (109) whichwas used without further purification.

A solution of sodium carbonate (37.8 mg, 0.36 mmol) in water (1.0 mL)was added whilst stirring to a suspension of(3R,3aR,6S,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (109)(assumed to be 0.162 mmol) in 1,4-dioxan (1.0 mL). A solution of9-fluorenylmethoxycarbonyl chloride (47.5 mg, 0.178 mmol) in 1,4-dioxan(1.0 mL) was added then the mixture stirred for 2 hours thendichloromethane (10 mL) was added and the mixture washed with water (10mL). The aqueous layer was re-extracted with dichloromethane (2×5 mL)then the combined organic layers dried (Na₂SO₄), filtered and reduced invacuo to leave a colourless oil (59 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 35:65 gavealcohol (2c′; R¹=Me) (48.1 mg, 81.3%) as a white solid. TLC (R_(f)=0.30,EtOAc:heptane 1:1), analytical HPLC single main peak, R_(t)=14.54 min.,HPLC-MS 366.2 [M+H]⁺, 388.2 [M+Na]⁺, 753.3 [2M+Na]⁺; [α]_(D) ²² −46.8°(c=4.81, CHCl₃); δ_(C) (125 MHz, CDCl₃) mixture of approximately 1:1rotamers, 16.67/16.97 (CHCH₃), 37.04/37.99 (CHCH₃), 47.31/47.55 (FmocCH), 51.49/51.74 (FmocNCH₂), 65.41/67.00 (Fmoc CH₂), 68.38/69.16°(FmocNCH), 73.81/74.04 (OCH₂CHOH), 76.26 (OCH₂CHOH), 87.23/87.82(OCHCHCH₃), 119.84, 119.93, 124.39, 124.42, 124.87, 126.94, 127.36,127.68, 127.80 and 127.83 (Fmoc aromatic CH), 141.21, 141.30, 141.38,143.67, 143.80, 143.90 and 143.94 (Fmoc quaternary), 154.40/155.34 (FmocC═O).

Preparation of (3aS,6S,6aR)-(9H-fluoren-9-yl)methyl6-methyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d′;R¹=Me)

Dess-Martin periodinane (99.2 mg, 0.234 mmol) was added to a stirredsolution of alcohol (2c′; R¹=Me) (42.7 mg, 0.117 mmol) indichloromethane (2 mL) under an atmosphere of argon. The mixture wasstirred for 2 hours then diluted with dichloromethane (15 mL). Theorganic phase was washed with a mixture of saturated aqueous sodiumbicarbonate and 0.25M sodium thiosulphate solution (1:1, 10 mL), thensaturated aqueous sodium bicarbonate (10 mL), then brine (10 mL), thendried (Na₂SO₄), filtered and reduced in vacuo. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 30:70 gaveketone (2d′; R¹=Me) (36.1 mg, 84.9%) as a white solid. TLC (R_(f)=0.35,EtOAc:heptane 1:1), analytical HPLC broad main peak, 14.2-16.2 min.,HPLC-MS 364.2 [M+H]⁺, 386.2 [M+Na]⁺, 404.1 [M+H₂O+Na]⁺, 749.2 [2M+Na]⁺;[α]_(D) ²² −127.0° (c=3.11, CHCl₃); δ_(C) (125 MHz, CDCl₃); 16.10(CH₃CH), 38.0 (CH₃CH), 48.0 (Fmoc-CH), 52.5 (FmocNCH₂), 61.5 (FmocNCH),68.0 (Fmoc-CH₂), 70.3 (OCH₂C═O), 87.3 (OCHCHCH₃), 120.0, 125.2, 126.5,127.5 (Fmoc aromatic CH), 141.0, 141.5, 143.5, 144.0 and 144.512 (Fmocquaternary), 154.8 (Fmoc C═O), 208.5 (ketone C═O).

Alternative Preparation of (3R,3aR,6S,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(110) (i) Preparation of (3R,3aR,6S,6aS)-tert-butyl6-bromo-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(111)

Lithium bromide (11.51 g, 132 mmol) was added to a stirred solution oftosylate (35b) (5.28 g, 13.2 mmol) in anhydrous DMF (75 mL) and themixture heated at 130° C. for 4 hours. The black solution was left tocool to ambient temperature then reduced in vacuo. The residue was takeninto DCM (100 mL) and washed with H₂O (100 mL). The organic layer wasdried (Na₂SO₄), filtered and reduced in vacuo to leave a black tar(Yield 3.3 g). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 5:95 to 30:70 gave bromide (111) (2.14 g,52.6%) as a pale green solid. TLC (R_(f)=0.4, EtOAc:heptane 3:1),analytical HPLC main peak, R_(t)=9.34 min., HPLC-MS 252.1/254.1[M+H−56]⁺, 308.1/310.1 [M+H]⁺; 330.0/332.0 [M+Na]⁺; [α]_(D) ²² −90.2°(c=2.33, CHCl₃); δ_(C) (125 MHz, CDCl₃) 28.35/28.44 ((CH₃)₃C),48.26/48.75 (BrCHCH), 53.48/54.14 (BocNCH₂), 67.78/68.29 (BocNCH),75.48/75.63 (OCH₂CHOH), 75.24/76.08 (OCH₂CHOH), 80.78/81.07 ((CH₃)₃Cquaternary), 87.01/87.85 (BrCHCH), 153.83/154.61 (Boc C═O).

(ii) Preparation of(3R,3aR,6S,6aS)-6-bromohexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride(112)

Bromide (111) (2.14 g, 6.95 mmol) was dissolved in 4N HCl/dioxan (30 mL)with stirring at ambient temperature. The purple solution was stirredfor 1 hour then reduced in vacuo and evaporated three times from diethylether to give a purple crystalline solid crude(3R,3aR,6S,6aS)-6-bromohexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride(112) (Yield 1730 mg) which was used without further purification.HPLC-MS 208.0/210.0 [M+H]⁺.

(iii) A solution of methyllithium (1.6M in diethyl ether, 29.25 mL, 46.8mmol) was added dropwise over 15 minutes to a stirred suspension ofcopper(I) bromide (3.36 g, 23.4 mmol) in tetrahydrofuran (30 mL) at 0°C. The mixture was stirred for 20 minutes then hydrochloride (112) (1.32g, 5.40 mmol) was added in portions over 8 minutes followed by asuspension of hydrochloride (112) (110 mg, 0.45 mmol) in tetrahydrofuran(10 mL) via cannula. The mixture was stirred for 1 hour 55 minutes thena solution of sodium carbonate (1.57 g, 14.8 mmol) in water (25 mL) wasadded dropwise over 3 minutes. The mixture was stirred for 15 minutesthen benzyl chloroformate (1.9 mL, 13.3 mmol) was added over 2 minutes.The mixture stirred for 45 minutes then water (200 mL) was added and themixture extracted with dichloromethane (3×50 mL). The combined organiclayers were mixed with brine (50 mL) then filtered through celite. Thefilter pad was washed with dichloromethane then the organic layerseparated, dried (Na₂SO₄), filtered and reduced in vacuo to leave abrown oil (2.78 g). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 55:45 gave (3R,3aR,6S,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3, 2-]pyrrole-4(5H)-carboxylate(110) (1.218 g, 75%) as a pale brown oil. TLC (R_(f)=0.30, EtOAc:heptane2:1), analytical HPLC main peak, R_(t)=9.890 min., HPLC-MS 278.1 [M+H]⁺,577.2 [2M+Na]⁺; [α]_(D) ²² −67.9° (c=5.08, CHCl₃); δ_(H) (500 MHz,CDCl₃) mixture of rotamers major:minor 2:1; 0.94 (3H, d, J=7.30 Hz,CH₃CH), 2.28-2.36 (1H, m, CH₃CH), 2.39-2.44 (0.33H, m, OH minor), 3.26(0.66H, brs, OH major), 3.28-3.48 (2H, m, CbzNCH₂), 3.68-3.75 (1H, m,1×OCH₂CHOH), 3.90 (0.33H, dd, J=9.99 and 4.27 Hz, 1×OCH₂CHOH minor),3.98 (0.66H, dd, J=9.74 and 4.85 Hz, 1×OCH₂CHOH major), 4.15 (1H, m,CbzNCH), 4.32-4.37 (1.33H, m, OCH₂CHOH minor and CH₃CHCH), 4.43-4.46(0.66H, m, OCH₂CHOH major), 5.09-5.24 (2H, m, CH₂Ph), 7.29-7.40 (5H, m,Cbz CH); δ_(C) (125 MHz, CDCl₃) 17.055 (CH₃CH), 37.510/38.042 (CH₃CH),51.928/52.011 (CbzNCH₂), 67.158/67.287 (CH₂Ph), 68.192/69.273 (CbzNCH),74.233 (OCH₂CHOH), 76.087 (OCH₂CHOH), 87.331/88.229 (CH₃CHCH), 127.764,127.898, 128.100, 128.261, 128.372, 128.521, 128.597 and 128.702(aromatic CH), 136.373/136.426 (Cbz quaternary), 154.649/155.529 (CbzC═O).

Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyl6-methyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d;R²=Me). Following Schemes 6 and 7 (i) Preparation of(3R,3aR,6R,6aS)-6-(tert butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-ol (86)

tert-Butyldimethylsilyl chloride (22.7 g, 151 mmol) was added to astirred solution of isomannide (40) (20.0 g, 137 mmol) and imidazole(21.0 g, 308 mmol) in dimethylformamide (150 mL). The mixture wasstirred for 1.25 hours then the majority of solvents were removed invacuo. The residue was partitioned between dichloromethane (400 mL) andwater (250 mL). The aqueous phase was reextracted with dichloromethane(100 mL) then the combined organic layers washed with a mixture of waterand brine (2.5:1 respectively, 2×350 mL). The organic phase was dried(Na₂SO₄), filtered and reduced in vacuo to leave a yellow oil (27.9 g).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 5:95 to 40:60 gave alcohol (86) as an oily white solid (14.1 g,39%). TLC (R_(f)=0.30, EtOAc heptane 1:2), HPLC-MS 261.2 [M+H]⁺, [α]_(D)²⁰+62.0° (c=3.065, CHCl₃); δ_(H) (500 MHz, CDCl₃) 0.09 and 0.10 (6Htotal, each s, Si(CH₃)₂), 0.89 (9H, s, SiC(CH₃)₃), 3.14 (1H, brs, OH),3.70-3.75 (2H, m, 1×CH₂CHOH and 1×CH₂CHOTBDMS), 3.90-3.96 (2H, m,1×CH₂CHOH and 1×CH₂CHOTBDMS), 4.17 (1H, brs, CHOH), 4.24 (1H, q, J=5.5Hz, CHOTBDMS), 4.39 (2H total, each t, J=5.5 Hz, CH₂OCHCHOCH₂); δ_(C)(125 MHz, CDCl₃) −5.159/−4.807 (Si(CH₃)₂), 18.337 (SiC(CH₃)₃), 25.774(SiC(CH₃)₃), 71.753 (CHOH), 73.392 (CHOTBDMS), 74.208 and 75.749(OCH₂CHOH and OCH₂CHOTBDMS), 81.523 and 82.039 (OCHCHO).

(ii) Preparation of(3aS,6R,6aS)-6-(tert-butyldimethylsilyloxy)tetrahydrofuro[3,2-b]furan-3(2H)-one(87)

Dess-Martin periodinane (31.18 g, 73.5 mmol) was added to a stirredsolution of alcohol (86) (9.56 g, 36.8 mmol) in dichloromethane (110 mL)under an atmosphere of argon. The mixture was stirred at 30-35° C. for 5hours, at ambient temperature for 16 hours, at 30-35° C. for 8 hours andat ambient temperature for 20 hours before adding Isolute® HM-N thenremoving the solvents in vacuo. Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 5:95 to 40:60 gave ketone(87) as a pale yellow oil (8.62 g, 91%).

(iii) Alternative preparation of(3aS,6S,6aS)-6-(tert-butyldimethylsilyloxy)tetrahydrofuro[3,2-b]furan-3(2H)-one(87)

A solution of dimethyl sulfoxide (0.65 mL, 9.23 mmol) in dichloromethane(2 mL) was added dropwise to a stirred solution of oxalyl chloride (0.38mL, 4.39 mmol) in dichloromethane (10 mL) at ≦−60° C. over 15 minutes.The mixture was stirred for 10 minutes then a solution of alcohol (86)(1.0 g, 3.85 mmol) in dichloromethane (10 mL) was added dropwise over 15minutes. The mixture was stirred for 15 minutes then triethylamine (2.68mL, 19.23 mmol) was added dropwise over 5 minutes. The cooling bath wasremoved then the mixture allowed to warm to ambient temperature. Aqueoussaturated ammonium chloride solution (15 mL) was added then the productextracted into diethyl ether (2×25 mL). The combined organic layers werewashed with water (2×20 mL), dried (MgSO₄), filtered and reduced invacuo to leave a pale yellow oil (964 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 5:95 to 35:65 gaveketone (87) as a colourless oil (869 mg, 88%). TLC (R_(f)=0.60,EtOAc:heptane 1:1), HPLC-MS 259.2 [M+H]⁺, [α]_(D) ^(19.5)+87.1° (c=2.01,CHCl₃).

(iv) Preparation oftert-butyldimethyl((3R,3aS,6aR)-6-methylenehexahydrofuro[3,2-b]furan-3-yloxy)silane(88)

A solution of n-butyl lithium (2.5M in hexanes, 0.46 mL, 1.16 mmol) wasadded to a stirred suspension of methyltriphenylphosphonium bromide (415mg, 1.16 mmol) in tetrahydrofuran (4 mL) at 0° C. under an atmosphere ofargon over 2 minutes. The mixture was stirred at ambient temperature for3 hours then a solution of ketone (87) (200 mg, 0.78 mmol) intetrahydrofuran (2.5 mL) added. The mixture was heated at reflux for1.25 hours then allowed to cool to ambient temperature. Water (10 mL)was added and the product extracted into diethyl ether (1×25 mL then1×10 mL). The combined organic layers were washed with water (10 mL),then brine (10 mL), dried (MgSO₄), filtered and reduced in vacuo toleave a brown oil (296 mg). Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 0:100 to 20:80 gave alkene (88) as acolourless oil (96 mg, 48%). TLC (R_(f)=0.80, EtOAc:heptane 1:2),analytical HPLC single main peak, R_(t)=16.502 min.; HPLC-MS 257.2[M+H]⁺, [α]_(D) ²¹ +142.2° (c=1.547, CHCl₃); δ_(H) (500 MHz, CDCl₃) 0.09and 0.10 (6H total, each s, Si(CH₃)₂), 0.89 (9H, s, SiC(CH₃)₃), 3.59(1H, t, J=8.22 Hz, 1×CH₂CHOTBDMS), 3.82 (1H, dd, J=8.39 and 6.30 Hz,1×CH₂CHOTBDMS), 4.22-4.26 (1H, m, CHOTBDMS), 4.31 (1H, d, J=12.99 Hz,1×CH₂C═CH₂), 4.37 (1H, t, J=4.82 Hz, CHCHOTBDMS), 4.53 (1H, d, J=12.99Hz, 1×CH₂C═CH₂), 4.73 (1H, dd, J=4.76 and 1.15 Hz, CHC═CH₂), 5.11-5.13and 5.28-5.30 (2H total, m, C═CH₂); δ_(C) (125 MHz, CDCl₃) −5.008/−4.801(Si(CH₃)₂), 18.386 (SiC(CH₃)₃), 25.866 (SiC(CH₃)₃), 71.043 and 72.181(CH₂CHOTBDMS and OCH₂C═CH₂), 74.073 (CHOTBDMS), 82.377 and 83.053(CH₂OCHCHOCH₂), 109.497 (C═CH₂), 148.610 (C═CH₂).

(v) Alternative preparation oftert-butyldimethyl((3R,3aS,6aR)-6-methylenehexahydrofuro[3,2-b]furan-3-yloxy)silane (88)

A stirred suspension of methyltriphenylphosphonium bromide (1.84 g, 5.16mmol) and potassium tert-butoxide (578 mg, 5.16 mmol) in tetrahydrofuran(15 mL) was heated at reflux under an atmosphere of argon for 3 hoursthen allowed to cool to ambient temperature. A solution of ketone (87)(888 mg, 3.44 mmol) in tetrahydrofuran (7.5 mL) was added then heatingat reflux continued for 2.25 hours. The mixture was diluted with water(30 mL) then the product extracted into diethyl ether (2×30 mL). Thecombined organic layers were washed with brine (25 mL), dried (MgSO₄),filtered and reduced in vacuo to leave residue (2.07 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 15:85 gave alkene (88) as a colourless oil (799 mg, 91%).

(vi) Preparation oftert-butyldimethyl((3R,3aS,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yloxy)silane(89a)

Ethanol (1.5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (20 mg) and alkene (88) (69 mg, 0.27 mmol) under an atmosphereof argon. The argon was replaced by hydrogen then the suspension wasstirred for 1.75 hours. The hydrogen was replaced by argon then mixturewas filtered through celite in vacuo. The filter cake was washed withethanol (10 mL) then the solvents removed in vacuo from the filtrate toleave a residue (69 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 0:100 to 25:75 gave a mixture oftert-butyldimethyl((3R,3aS,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yloxy)silane(89a) andtert-butyldimethyl((3R,3aS,6S,6aR)-6-methylhexahydrofuro[3,2-b]furo-3-yloxy)silane(89b) (9:1 respectively) as a colourless oil (51 mg, 74%). Data for(89a): TLC (R_(f)=0.80, EtOAc:heptane 1:2.5), HPLC-MS 259.2 [M+H]⁺,[α]_(D) ²¹+86.8° (e=2.651, CHCl₃); δ_(H) (500 MHz, CDCl₃) 0.07 and 0.09(6H total, each s, Si(CH₃)₂), 0.88 (9H, s, SiC(CH₃)₃), 1.03 (3H, d,J=6.84 Hz, CH₃CH), 2.16-2.23 (1H, m, CH₃CH), 3.36 (1H, dd, J=1.1.14 and8.13 Hz, 1×CH₂CHCH₃), 3.48 (1H, dd, J=8.42 and 7.34 Hz, 1×CH₂CHOTBDMS),3.76 (1H, dd, J=8.52 and 6.19 Hz, 1×CH₂CHOTBDMS), 3.95 (1H, t, J=7.88Hz, 1×CH₂CHCH₃), 4.23-4.27 (1H, m, CHOTBDMS), 4.32 and 4.35 (2H total,each t, J=4.50 Hz and t, J=4.55 Hz respectively, CH₂OCHCHOCH₂); δ_(C)(125 MHz, CDCl₃) −5.039/−4.768 (Si(CH₃)₂), 9.084 (CH₃CH), 18.396(SiC(CH₃)₃), 25.876 (SiC(CH₃)₃), 39.892 (CH₃CH), 72.918 and 75.084(CH₂CHOTBDMS and OCH₂CHCH₃), 74.488 (CHOTBDMS), 83.196 and 84.697(CH₂OCHCHOCH₂).

(vii) Alternative preparation oftert-butyldimethyl((3R,3aS,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yloxy)silane(89a)

Ethyl acetate (5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (50 mg) and (89a) (799 mg, 3.12 mmol) under an atmosphere ofargon. The argon was replaced by hydrogen then the suspension wasstirred for 1 hour 25 minutes before replacing the hydrogen with argon,adding water (2 mL) then filtering the mixture through celite in vacuo.The filter cake was washed with ethyl acetate (40 mL) then the solventsremoved in vacuo from the filtrate to leave a colourless oil (795 mg).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 20:80 gave a mixture oftert-butyldimethyl((3R,3aS,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yloxy)silane(89a) andtert-butyldimethyl((3R,3aS,6S,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yloxy)silane(89b) (12:1 respectively) as a colourless oil (769 mg, 96%).

(viii) Preparation of(3R,3aR,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-ol (90a)

Tetrabutylammonium fluoride solution (1.0M in tetrahydrofuran, 2.65 mL,2.65 mmol) was added to a stirred solution of (89a) and (89b) (9:1respectively, 342 mg, 1.33 mmol) in tetrahydrofuran (2.5 mL). Thesolution was stirred for 50 minutes then water (20 mL) added. Theproduct was extracted into dichloromethane (2×10 mL) then the combinedorganic phases washed with brine (10 mL), dried (Na₂SO₄), filtered andreduced in vacuo to leave residue (158 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 20:80 to 50:50 gavea mixture of alcohol (90a) and(3R,3aR,6S,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-ol (90b) (11:1respectively) as a colourless oil (66 mg, 35%). Data for(3R,3aR,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-ol (90a): TLC(R_(f)=0.35, EtOAc:heptane 1:1), HPLC-MS 145.1 [M+H]⁺, 167.1 [M+Na]⁺,311.1 [2M+Na]⁺, [α]_(D) ^(21.5)+65.9° (c=2.58, CHCl₃); δ_(H) (500 MHz,CDCl₃) 1.08 (3H, d, J=6.83 Hz, CH₃CH), 2.25-2.35 (1H, m, CH₃CH), 2.77(1H, brs, OH), 3.36 (1H, dd, J=11.40 and 8.03 Hz, 1×CH₂CHCH₃), 3.58 (1H,dd, J=9.56 and 5.26 Hz, 1×CH₂CHOH), 3.81 (1H, dd, J=9.56 and 5.70 Hz,1×CH₂CHOH), 4.03 (1H, t, J=7.86 Hz, 1×CH₂CHCH₃), 4.25 (1H, dd, J=11.09and 5.56 Hz, CHOH), 4.33 and 4.51 (2H total, t, J=4.49 Hz and dd, J=5.64and 4.39 Hz respectively, CH₂OCHCHOCH₂); δ_(C) (125 MHz, CDCl₃) 8.948(CH₃CH), 39.976 (CH₃CH), 72.459 (CHOH), 74.564 and 74.921 (CH₂CHOH) andOCH₂CHCH₃), 83.095 and 84.958 (CH₂OCHCHOCH₂).

(ix) Preparation of(3R,3aS,6R,6aR)-6-methylhexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (91a)

Tetrabutylammonium fluoride solution (1.0M in tetrahydrofuran, 18.5 mL,18.5 mmol) was added to a stirred solution of alcohols (90a) and (90b)(7:1 respectively, 4.345 g, 16.84 mmol) in tetrahydrofuran (20 mL). Thesolution was stirred for 1 hour 25 minutes then dichloromethane (200 mL)was added. The solution was dried (Na₂SO₄), filtered and the majority ofsolvents removed in vacuo. Pyridine (30 mL) was added followed byp-toluenesulfonyl chloride (12.8 g, 67.4 mmol). The mixture was stirredunder an atmosphere of argon for 20 hours then diluted with water (300mL). The product was extracted into tert-butyl methyl ether (2×200 mL)then dried (MgSO₄), filtered and reduced in vacuo to leave a residue.Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 35:65 gave a mixture of tosylates (91a) and (91b)(approximately 7:1 respectively) as a pale yellow oil (4.47 g, 89%).Data for (91a); TLC (R_(f)=0.20, EtOAc:heptane 1:3), HPLC-MS 299.1[M+H]⁺, 316.2, 619.2 [2M+Na]⁺, [α]_(D) ²²+84.8° (c=3.065, CHCl₃); δ_(H)(500 MHz, CDCl₃) 1.03 (3H, d, J=6.84 Hz, CH₃CH), 2.18-2.27 (1H, m,CH₃CH), 2.43 (3H, s, aryl-CH₃), 3.34 (1H, dd, J=11.28 and 8.31 Hz,1×CH₂CHCH₃), 3.70 (1H, dd, J=9.61 and 6.62 Hz, 1×CH₂CHOTs), 3.84 (1H,dd, J=9.61 and 6.24 Hz, 1×CH₂CHOTs), 3.95 (1H, t, J=8.01 Hz,1×CH₂CHCH₃), 4.32 and 4.50 (2H total, t, J=4.54 Hz and t, J=4.74 Hzrespectively, CH₂OCHCHOCH₂), 4.88 (1H, dd, J=11.6 and 6.42 Hz, CHOTs),7.33 (2H, brd, J=8.01 Hz, aromatic CH₃CCH), 7.82 (2H, brd, J=8.34 Hz,aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 8.841 (CH₃CH), 21.669(aryl-CH₃), 39.786 (CH₃CH), 70.301 and 75.096 (CH₂CHOTs and CH₂CHCH₃),79.422 (CHOTs), 81.409 and 84.859 (CH₂OCHCHOCH₂), 127.976 and 129.806(aromatic CH), 133.392/133.426 (CHOSO₂C quaternary), 144.966 (CH₃Cquaternary).

(x) Preparation of(3S,3aS,6R,6aR)-3-bromo-6-methylhexahydrofuro[3,2-b]furan (92)

A stirred mixture of lithium bromide (596 mg, 6.85 mmol) and tosylate(91a) (0.68 g, 2.28 mmol) in dimethylformamide (5 mL) was heated at 110°C. for 1 hour, then at 125° C. for 1.5 hours, then at 130° C. for 2hours under an atmosphere of argon then diluted with water (20 mL). Theproduct was extracted into diethyl ether (4×10 mL) then the combinedorganic layers washed with water (3×10 mL), brine (10 mL), dried(MgSO₄), filtered and reduced in vacuo to leave an orange oil. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 35:65 gave bromide (92) as a colourless oil (292 mg, 62%). TLC(R_(f)=0.80, EtOAc:heptane 1:2), [α]_(D) ^(20.5)+75.2° (c=1.13, CHCl₃);δ_(H) (500 MHz, CDCl₃) 1.10 (3H, d, J=6.80 Hz, CH₃CH), 2.24-2.33 (1H, m,CH₃CH), 3.30 (1H, dd, J=11.23 and 8.20 Hz, 1×CH₂CHCH₃), 4.13 (2H, m,CH₂CHBr), 4.20 (1H, t, J=7.99 Hz, 1×CH₂CHCH₃), 4.28-4.30 (1H, m, CHBr),4.68 and 4.74 (2H total, t, J=3.87 Hz and dd, J=3.55 and 0.92 Hzrespectively, BrCHCHCHO); δ_(C) (125 MHz, CDCl₃) 9.842 (CH₃CH), 39.904(CH₃CH), 51.616 (CHBr), 74.993 and 76.118 (CH₂CHBr and CH₂CHCH₃), 84.708and 89.891 (BrCHCHCHO).

(xi) Preparation of (R)-2-((S)-2,5-dihydrofuran-2-yl)propylmethanesulfonate (93)

A solution of ammonium chloride (94 mg, 1.76 mmol) in water (1.1 mL)then zinc dust (176 mg, 2.71 mmol) were added consecutively to asolution of bromide (92) (280 mg, 1.35 mmol) in tetrahydrofuran (4.5mL). The mixture was stirred for 2 hours 10 minutes before filtering thesuspension through celite in vacuo. The filter cake was washed withdiethyl ether (10 mL) then the filtrate washed with hydrochloric acid(1M, 10 mL). The aqueous layer was reextracted with diethyl ether (10mL) then the combined organic layers were washed with brine (10 mL),then dried (MgSO₄), filtered and the majority of solvents removed invacuo to leave a residue. Triethylamine (0.292 mL, 2.10 mmol) thenmethanesulfonyl chloride (0.167 mL, 2.16 mmol) were added to the residuethen the suspension stirred for 1.5 hours before adding triethylamine(0.097 mL, 0.89 mmol) and methanesulfonyl chloride (0.056 mL, 0.72mmol). The suspension was stirred for 40 minutes then diluted withdichloromethane (15 mL), washed with water (10 mL), brine (10 mL), dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue (225 mg).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 40:60 gave mesylate (93) as a colourless oil (111 mg,40%). TLC (R_(f)=0.60, EtOAc:heptane 1:1), analytical HPLC single mainpeak, R_(t)=7.028 min; HPLC-MS 207.1 [M+H]⁺, 224.1, 435.1 [2M+Na]⁺;δ_(H) (500 MHz, CDCl₃) 1.03 (3H, d, J=6.93 Hz, CH₃CH), 1.97-2.06 (1H, m,CH₃CH), 3.00 (3H, s, OSO₂CH₃), 4.17 (1H, dd, J=9.61 and 6.39 Hz,1×CH₂OMs), 4.28 (1H, dd, J=9.61 and 4.52 Hz, 1×CH₂OMs), 4.60-4.64 (2H,m, OCH₂CH═CH), 4.69-4.74 (1H, m, OCHCH═CH), 5.82-5.85 and 5.94-5.98 (2Htotal, m, CH═CH); δ_(C) (125 MHz, CDCl₃) 13.088 (CH₃CH), 37.062(OSO₂CH₃), 38.829 (CH₃CH), 71.933 (CH₂OMs), 75.361 (0 CH₂CH═CH), 86.908(OCHCH═CH), 127.345 and 127.877 (CH═CH).

(xii) Alternative preparation of (R)-2-((S)-2,5-dihydrofuran-2-yl)propylmethanesulfonate (93)

A stirred mixture of lithium bromide (773 mg, 8.89 mmol) and tosylate(91) (662 mg, 2.22 mmol) in dimethylformamide (4.5 mL) was heated at125° C. for 3 hours under an atmosphere of argon then diluted with water(15 mL). The product was extracted into tert-butyl methyl ether (4×5 mL)then the organic phase washed with water (3×5 mL), brine (5 mL), dried(MgSO₄), filtered and reduced in vacuo to leave bromide (92) as a brownoil (411 mg) which was used without further purification.

A solution of ammonium chloride (154 mg, 2.89 mmol) in water (1.5 mL)then zinc dust (289 mg, 4.44 mmol) were added consecutively to asolution of bromide (92) (prepared as above, assumed to be 2.22 mmol) intetrahydrofuran (6 mL). The mixture was stirred for 19 hours beforefiltering the suspension through celite in vacuo. The filter cake waswashed with diethyl ether (15 mL). A mixture of brine and 1Mhydrochloric acid (1:1, 15 mL) was added to the filtrate then theorganic phase separated. The aqueous layer was reextracted with diethylether (15 mL) then the combined organic layers were washed with brine(10 mL), then dried (MgSO₄), filtered and the majority of solventsremoved in vacuo to leave a residue. Dichloromethane (2 mL) was added tothe residue followed by triethylamine (0.618 mL, 4.44 mmol) thenmethanesulfonyl chloride (0.334 mL, 4.44 mmol). The suspension wasstirred for 2.25 hours then triethylamine (0.309 mL, 2.22 mmol) andmethanesulfonyl chloride (0.172 mL, 2.22 mmol) added. The suspension wasstirred for 2.75 hours then triethylamine (0.155 mL, 1.11 mmol) andmethanesulfonyl chloride (0.86 mL, 1.11 mmol) added. The suspension wasstirred for 50 minutes then diluted with dichloromethane (25 mL), washedwith water (10 mL), brine (10 mL), dried (Na₂SO₄), filtered and reducedin vacuo to leave a pale yellow oil (724 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 0:100 to 30:70 gavemesylate (93) as a colourless oil (260 mg, 57%).

(xiii) Preparation of Benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)propylcarbamate (95)

A stirred mixture of mesylate (93) (68 mg, 0.33 mmol), ammoniumhydroxide (0.8 mL) and ammonia in propan-2-ol (2M, 0.4 mL, 0.8 mmol) washeated at 70° C. in a sealed tube for 2 hours. The mixture was stirredat ambient temperature for 18 hours then the majority of the solventswere removed in vacuo. The residue was azeotroped with diethyl ether(3×3 mL) to obtain amine (94) which was used without furtherpurification.

1,4-Dioxan (0.7 mL) then a solution of sodium carbonate (87 mg, 0.83mmol) in water (0.6 mL) was added whilst stirring to the crude amine(94) amine (assumed to be 0.33 mmol) followed by benzylchloroformate(0.11 mL, 0.73 mmol). The mixture was stirred for 50 minutes beforeadding dichloromethane (5 mL) and water (10 mL). The organic phase wasseparated and the aqueous reextracted with dichloromethane (2×5 mL). Thecombined organic layers were washed with brine (5 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a residue. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 25:75 gave benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)propylcarbamate (95) as a colourless oil (31 mg, 36%). TLC (R_(f)=0.45,EtOAc:heptane 2:3), analytical HPLC single main peak, R_(t)=13.127 min;HPLC-MS 262.1 [M+H]⁺, 545.2 [2M+Na]⁺, [α]_(D) ²³ −58.7° (c=2.81, CHCl₃);δ_(H) (500 MHz, CDCl₃) 0.93 (3H, d, J=6.93 Hz, CH₃CH), 1.73-1.81 (1H, m,CH₃CH), 3.18-3.24 (2H, m, CH₂NH), 4.55-4.68 (3H, m, CH₂CH═CHCH), 5.08(2H, brs, CH₂Ph), 5.38 (0.7H, brs, NH), 5.81-5.84 and 5.91-5.94 (2Htotal, m, CH═CH), 7.28-7.36 (5H, m, aromatic-CH); δ_(C) (125 MHz, CDCl₃)14.404 (CH₃CH), 38.844 (CH₃CH), 44.727 (CH₂NH), 66.511 (CH₂Ph), 75.206(OCH₂CH═CH), 90.150 (OCHCH═CH), 127.434, 128.017, 128.059, 128.097 and128.468 and 127.877 (CH═CH and aromatic CH), 136.745 (Cbz quaternary),156.509 (Cbz C═O).

(xiv) Alternative preparation of(R)-2-((S)-2,5-dihydrofuran-2-yl)propan-1-amine (94)

Sodium azide (37 mg, 0.58 mmol) was added to a stirred solution ofmesylate (93) (108 mg, 0.52 mmol) in dimethylformamide (1 mL) then themixture heated at 60° C. under an atmosphere of argon for 6.25 hours.The mixture was stood at ambient temperature for 18 hours then sodiumazide (5 mg, 0.08 mmol) was added. The mixture heated at 60° C. under anatmosphere of argon for 2.75 hours then water (0.1 mL) andtriphenylphosphine (206 mg, 0.79 mmol) were added. The mixture stirredat 45-55° C. for 3.5 hours. HPLC-MS indicated the appearance of a newpeak corresponding to amine (94) together with other products.

(xv) Preparation of benzyl(R)-2-((1R,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)propylcarbamate (96)

To a solution of benzyl (R)-2-((S)-2,5-dihydrofuran-2-yl)propylcarbamate (95) (215 mg, 0.82 mmol) in acetonitrile (6 mL) and aqueousNa₂.EDTA (0.4 mmol solution, 6 mL) at 0° C. was added1,1,1-trifluoroacetone (1.34 mL, 9.89 mmol). To this solution was addedin portions a mixture of sodium bicarbonate (0.58 g, 6.92 mmol) andOXONE® (1.57 g, 2.55 mmol) over a period of 1 hour. The mixture wasstirred for 40 minutes then diluted with water (25 mL) and the productextracted into dichloromethane (2×15 mL). The combined organic layerswere washed consecutively with water (10 mL), aqueous sodium hydrogensulphite solution (5%, 10 mL) and water (10 mL), then dried (Na₂SO₄),filtered and reduced in vacuo to leave a colourless oil (218 mg). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 50:50 gave anti-(96), syn-(96) and anti-(96b), (approximately3.5:1:0.5 respectively) as a colourless oil (100 mg, 44%). Data foranti-(96); TLC (R_(f)=0.45, EtOAc:heptane 55:45), analytical HPLC mainpeak, R_(t)=10.381 min., HPLC-MS 278.1 [M+H]⁺, 300.1 [M+Na]⁺, 577.2[2M+Na]⁺; δ_(H) (500 MHz, CDCl₃) 0.97 (3H, d, J=6.81 Hz, CH₃CH),1.68-1.73 (1H, m, CH₃CH), 3.20-3.27 (2H, m, CH₂NH), 3.63-3.75, 3.83 and3.96 (3H, 1H and 1H respectively, m, d, J=8.96 Hz and d, J=10.53 Hzrespectively, OCH₂CHCHCH), 5.08 (2H, brs, CH₂Ph), 5.23 (1H brs, NH),7.28-7.36 (5H, m, aromatic CH); δ_(C) (125 MHz, CDCl₃) 14.523 (CH₃CH),34.893 (CH₃CH), 44.771 (CH₂NHCbz), 56.132 and 58.001 (OCH₂CHCH), 66.623(CH₂Ph), 67.623 (OCH₂CH), 81.732 (OCHCHCH₃), 128.103, 128.458 and128.503 (aromatic CH), 136.576 (Cbz quaternary), 156.526 (Cbz C═O).

(xvi) Preparation of (3R,3aR,6R,6aR)-benzyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(108)

To a solution of epoxide mixture (96) (90 mg, assuming 0.32 mmol) inanhydrous THF (3 mL) was added sodium hydride (1.3 eq, 60% dispersion inparaffin oil, 0.42 mmol, 17.0 mg) and the mixture stirred at ambienttemperature under argon. After 2 hour a further aliquot of sodiumhydride (0.3 eq, 4 mg) was added and stirring continued for 30 mins. Thereaction mixture was diluted with DCM (25 mL), washed with saturatedbrine (25 mL), dried (Na₂SO₄), filtered and reduced in vacuo to a tangum (110 mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 20:80 to 50:50 gave bicyclic alcohol (108) as aclear gum (53.0 mg, 59.7%). TLC (R_(f)=0.40, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=10.87 min., HPLC-MS 278.1[M+H]⁺, 300.1 [M+Na]⁺, 577.2 [2M+Na]⁺; [α]_(D) ²² −44.6° (c=3.7, CHCl₃);δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 2:1; 1.08 (2H, d,J=6.85 Hz, CH₃CH major), 1.10 (1H, d, J=6.93 Hz, CH₃CH minor), 2.10-2.21(1H, m, CH₃CH), 2.68 (1H, brs, OH), 2.85 (1H, dd, J=21.67 and 10.77 Hz,1×CbzNCH₂), 3.71 (0.66H, dd, J=10.50 and 8.02 Hz, 1×CbzNCH₂ major),3.71-3.76 (1H, m, 1×OCH₂CHOH), 3.80 (0.33H, dd, J=10.62 and 8.10 Hz,1×CbzNCH₂ minor), 3.85 (0.33H, dd, J=9.98 and 4.13 Hz, OCH₂CHOH minor),3.93 (0.66H, dd, J=9.82 and 4.69 Hz, 1×OCH₂CHOH major), 4.18 (1H, d,J=4.42 Hz, CbzNCH), 4.32-4.37 (0.33H, m, OCH₂CHOH minor), 4.43 (0.66H,brt, J=3.52 Hz, OCH₂CHOH major), 4.49-4.53 (1H, m, CH₃CHCH), 5.06-5.21(2H, m, CH₂Ph), 7.29-7.38 (5H, m, Cbz CH); δ_(C) (125 MHz, CDCl₃)11.136/11.155 (CH₃CH), 37.394/37.707 (CH₃CH), 51.255/51.522 (CbzNCH₂),67.123/67.180 (CH₂Ph), 69.977/71.069 (CbzNCH), 74.503/74.637 (OCH₂CHOH),76.302/77.222 (OCH₂CHOH), 83.713/84.583 (CH₃CHCH), 127.900, 127.945,128.117, 128.221, 128.518, 128.661 and 128.696 (aromatic CH),136.385/136.483 (Cbz quaternary), 154.079/154.828 (Cbz C═O).

(xvii) Preparation of (3R,3aR,6R,6aR)-(9H-fluoren-9-yl)methyl3-hydroxy-6-methyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c; R²=Me)

Methanol (1.25 mL) was added dropwise to a mixture of 10% palladium oncharcoal (20 mg) and bicyclic alcohol (108) (49 mg, 0.177 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1 hour then filtered through celite in vacuo.The filter cake was washed with ethanol (10 mL) then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withdiethyl ether (3×3 mL) to obtain the crude(3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107) whichwas used without further purification.

A solution of sodium carbonate (41 mg, 0.389 mmol) in water (0.5 mL) wasadded whilst stirring to a suspension of(3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107)(assumed to be 0.177 mmol) in 1,4-dioxan (0.4 mL). A solution of9-fluorenylmethoxycarbonyl chloride (50 mg, 0.195 mmol) in 1,4-dioxan(0.6 mL) was added then the mixture stirred for 19.5 hours thendichloromethane (10 mL) was added and the mixture washed with water (10mL). The aqueous layer was re-extracted with dichloromethane (2×5 mL)then the combined organic layers dried (Na₂SO₄), filtered and reduced invacuo to leave a colourless oil (80 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 40:60 gavealcohol (2c; R²=Me) (55.35 mg, 85%) as a white solid. TLC (R_(f)=0.33,EtOAc heptane 1:1), analytical HPLC single main peak, R_(t)=14.961 min.,HPLC-MS 366.2 [M+H]⁺, 388.1 [M+Na]⁺, 753.3 [2M+Na]⁺; [α]_(D) ²² −34.6°(c=4.92, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor55:45; 0.96 (0.55H, d, J=3.66 Hz, OH major), 1.00 (1.65H, d, J=6.82 Hz,CH₃CH major), 1.12 (1.35H, d, J=6.82 Hz, CH₃CH minor), 1.92-2.01 (0.55H,m, CH₃CH major), 2.15-2.24 (0.45H, m, CH₃CH minor), 2.46 (0.45H, d,J=3.52 Hz, OH minor), 2.67 (0.55H, t, J=11.10 Hz, 1×FmocNCH₂ major),2.86 (0.45H, t, J=10.84 Hz, 1×FmocNCH₂ minor), 3.43 (0.55H, d, J=4.44Hz, FmocNCH major), 3.45-3.52 (1.10H, m, OCH₂CHOH major and 1×OCH₂CHOHmajor), 3.58-3.69 (1.55H, m, 1×FmocNCH₂ and 1×OCH₂CHOH major), 3.72(0.45H, dd, J=9.80 and 3.46 Hz, 1×OCH₂CHOH minor), 3.93 (0.45H, dd,J=9.75 and 4.85 Hz, 1×OCH₂CHOH minor), 4.16 (0.45H, brd, J=4.68 Hz,FmocNCH minor), 4.20-4.24 (1H, m, Fmoc CH), 4.26 (0.55H, t, J=3.78 Hz,OCHCHCH₃ major), 4.36-4.47 (1.35H, m, Fmoc CH₂ minor and OCH₂CHOHminor), 4.50 (0.45H, t, J=4.38 Hz, OCHCHCH₃ minor), 4.74 (0.55H, dd,J=10.85 and 3.84 Hz, 1×Fmoc CH₂ major), 4.79 (0.55H, dd, J=10.85 and4.14 Hz, 1×Fmoc CH₂ major), 7.29-7.80 (8H, Fmoc aromatic CH); δ_(C) (125MHz, CDCl₃) 11.039/11.159 (CHCH₃), 37.080/37.663 (CHCH₃), 47.315/47.450(Fmoc CH), 51.051/51.109 (FmocNCH₂), 65.517/67.255 (Fmoc CH₂),70.319/71.071 (FmocNCH), 74.235/74.296 (OCH₂CHOH), 76.628/76.913(OCH₂CHOH), 83.679/84.293 (OCHCHCH₃), 119.880, 119.903, 119.998,124.431, 124.957, 124.991, 127.026, 127.408, 127.432, 127.739, 127.748,127.839 and 127.889 (Fmoc aromatic CH), 141.243, 141.327, 141.349,141.428, 143.765, 143.915, 143.982 and 144.047 (Fmoc quaternary),153.854/154.783 (Fmoc C═O).

(xviii) Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyloxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d; R²=Me)

Dess-Martin periodinane (114 mg, 0.269 mmol) was added to a stirredsolution of alcohol (2c; R²=Me) (49 mg, 0.134 mmol) in dichloromethane(1.25 mL) under an atmosphere of argon. The mixture was stirred for 22hours then diluted with dichloromethane (15 mL). The organic phase waswashed with a mixture of saturated aqueous sodium bicarbonate and 0.25Msodium thiosulphate solution (1:1, 5 mL), then saturated aqueous sodiumbicarbonate (5 mL), then brine (5 mL), then dried (Na₂SO₄), filtered andreduced in vacuo. Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 15:85 to 40:60 gave ketone (2d; R²=Me) (42 mg,87%) as a white solid. TLC (R_(f)=0.35, EtOAc heptane 1:1), analyticalHPLC broad main peak, R_(t)=14.720 min., HPLC-MS 364.2 [M+H]⁺, 386.2[M+Na]⁺, 404.2 [M+H₂O+Na]⁺, 749.3 [2M+Na]⁺; [α]_(D) ²² −135.2° (c=3.55,CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers 1:1; 1.18 (3H, d,J=6.81 Hz, CH₃CH), 2.23-2.33 (1H, m, CH₃CH), 3.08 (1H, t, J=10.90 Hz,1×FmocNCH₂), 3.79 (0.5H, brt, J=9.01 Hz, 0.5×FmocNCH₂), 3.93-4.01 (1.5H,m, 0.5×FmocNCH₂ and 1×OCH₂C═O), 4.14-4.59 (5H, m, 1×OCH₂C═O, FmocNCH,Fmoc-CH₂ and Fmoc-CH), 4.64 (1H, brs, 0.5×OCHCHCH₃), 4.69 (1H, brs,0.5×OCHCHCH₃), 7.29-7.79 (8H, Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃);10.070/10.136 (CH₃CH), 37.729/38.240 (CH₃CH), 47.192/47.268 (Fmoc-CH),51.013/51.318 (FmocNCH₂), 62.596/63.082 (FmocNCH), 67.623/68.209(Fmoc-CH₂), 70.425/71.006 (OCH₂C═O), 83.680/84.582 (OCHCHCH₃),119.883/119.954/124.989/125.166/125.501/127.056/127.634 and 127.694(Fmoc aromatic CH), 141.239, 141.320, 143.655, 143.774, 143.983 and144.512 (Fmoc quaternary), 154.753/154.813 (Fmoc C═O), 208.738/208.858(ketone C═O).

Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyl6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d; R²CHF₂). Following Schemes 8 and 9 (i) Preparation oftert-butyl((3R,3aS,6aR)-6-(difluoromethylene)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(97)

A solution of triphenylphosphine (13.30 g, 50.8 mmol) inN,N-dimethylacetamide (35 mL) was added to a stirred suspension ofketone (87) (6.55 g, 25.4 mmol) and dibromodifluoromethane (4.64 mL,50.8 mmol) in N,N-dimethylacetamide (40 mL) at 0° C. under an atmosphereof argon dropwise over 1.25 hours. The mixture was stirred at ambienttemperature for 1.25 hours then zinc dust (3.30 g, 50.8 mmol) was addedover 5 minutes. The mixture was stirred at ambient temperature for 20minutes then heated at 70° C. for 4 hours then stirred at ambienttemperature for 18 hours. The mixture was diluted with diethyl ether(200 mL) then filtered through celite. The filter cake was washed withdiethyl ether (200 mL) then water (400 mL) was added to the filtrate.The mixture was separated then the aqueous re-extracted with diethylether (250 mL). The combined organic layers were washed with brine (250mL), dried (Na₂SO₄), filtered and reduced in vacuo to leave anorange-brown solid (15.8 g). Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 0:100 to 10:90 gave alkene (97) as acolourless oil (4.84 g, 65%). TLC (R_(f)=0.75, EtOAc:heptane 1:4),HPLC-MS 156.1, 293.1 [M+H]⁺, [α]_(D) ²²+135.6° (c=2.175, CHCl₃); δ_(H)(500 MHz, CDCl₃) 0.09 and 0.10 (6H total, each s, Si(CH₃)₂), 0.90 (9H,s, SiC(CH₃)₃), 3.61 (1H, dd, J=8.59 and 7.63 Hz, 1×CH₂CHOTBDMS), 3.84(1H, dd, J=8.72 and 6.05 Hz, 1×CH₂CHOTBDMS), 4.23 (1H, dt, J=7.48 and5.63 Hz, CHOTBDMS), 4.41-4.46 (2H, m, 1×CH₂C═CF₂ and CHCHOTBDMS),4.54-4.59 (1H, ddd, J=12.29, 4.19 and 0.74 Hz, 1×CH₂C═CF₂), 5.11 (1H,brdt, J=5.05 and 1.28 Hz, CHC═CF₂); δ_(C) (125 MHz, CDCl₃) −5.064/−4.811(Si(CH₃)₂), 18.342 (SiC(CH₃)₃), 25.817 (SiC(CH₃)₃), 67.479/67.491/67.501and 67.513 (CH₂C═CF₂), 71.680 (CH₂CHOTBDMS), 73.257 (CHOTBDMS),79.668/79.692/79.718 and 79.741 (CHC═CF₂), 83.104 (CHCHOTBDMS),91.167/91.334 and 91.501 (C═CF₂), 148.892/151.193 and 153.492 (C═CF₂).

(ii) Preparation of tert-Butyl((3R,3aS,6R,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane (98a) andtert-butyl((3R,3aS,6S,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98b)

Methanol (5 mL) was added dropwise to 10% palladium on charcoal (450 mg)followed by a solution of alkene (97) (4.84 g, 16.6 mmol) in methanol(20 mL) under an atmosphere of argon at 0° C. The argon was replaced byhydrogen then the suspension was stirred at ambient temperature for 3hours 50 minutes. The hydrogen was replaced by argon then mixture wasfiltered through celite in vacuo. The filter cake was washed withethanol (100 mL) then the solvents removed in vacuo from the filtrate toleave a residue. NMR analysis of the residue indicated a mixture oftert-butyl((3R,3aS,6R,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98a) andtert-butyl((3R,3aS,6S,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98b) (approximately 4.5:1 respectively) to be present. Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 10:90 gave (in order of elution)tert-butyl((3R,3aS,6R,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98a) as a colourless oil (3.55 g, 73%), andtert-butyl((3R,3aS,6S,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98b) as a colourless oil (446 mg, 9%). Data for (98a); TLC (R_(f)=0.50,EtOAc:heptane 1:4), HPLC-MS 156.1, 295.1 [M+H]⁺; [α]_(D) ²² +67.7°(c=2.068, CHCl₃); δ_(H) (500 MHz, CDCl₃) 0.09 and 0.10 (6H total, eachs, Si(CH₃)₂), 0.90 (9H, s, SiC(CH₃)₃), 2.61-2.71 (1H, m, CHCHF₂), 3.64(1H, dd, J=8.86 and 6.16 Hz, 1×CH₂CHOTBDMS), 3.76 (1H, dd, J=8.86 and5.75 Hz, 1×CH₂CHOTBDMS), 3.84 (1H, brt, J=9.87 Hz, 1×CH₂CHCHF₂), 4.03(1H, t, J=8.47 Hz, 1×CH₂CHCHF₂), 4.28 (1H, dd, J=10.90 and 5.90 Hz,CHOTBDMS), 4.45 (1H, t, J=4.69 Hz, CHCHOTBDMS), 4.59 (1H, t, J=4.83 Hz,CHCHCHF₂), 5.99 (1H, ddd, J=56.95, 55.33 and 7.44 Hz, CHF₂); δ_(C) (125MHz, CDCl₃) −5.107/−4.796 (Si(CH₃)₂), 18.364 (SiC(CH₃)₃), 25.748/25.830(SiC(CH₃)₃), 49.277/49.451 and 49.625 (CHCHF₂), 68.618/68.693(CH₂CHOTBDMS), 73.573 (CH₂CHCHF₂), 73.777 (CHOTBDMS), 81.807/81.879(CHCHCHF₂), 84.018 (CHCHOTBDMS), 114.408/116.289/116.318 and 118.198(CHF₂). Data for (98b); TLC (R_(f)=0.46, EtOAc heptane 1:4), HPLC-MS156.1, 295.1 [M+H]⁺, [α]_(D) ²² +70.9° (c=1.833, CHCl₃); δ_(H) (500 MHz,CDCl₃) 0.10 and 0.11 (6H total, each s, Si(CH₃)₂), 0.90 (9H, s,SiC(CH₃)₃), 2.64-2.75 (1H, m, CHCHF₂), 3.64 (1H, dd, J=8.97 and 6.15 Hz,1×CH₂CHOTBDMS), 3.75 (1H, dd, J=8.97 and 5.57 Hz, 1×CH₂CHOTBDMS), 3.95(1H, dd, J=9.49 and 4.01 Hz, 1×CH₂CHCHF₂), 4.03 (1H, brt, J=8.19 Hz,1×CH₂CHCHF₂), 4.23 (1H, dd, J=11.37 and 5.58 Hz, CHOTBDMS), 4.39 (1H, t,J=5.20 Hz, CHCHOTBDMS), 4.60 (1H, dd, J=5.16 and 1.47 Hz, CHCHCHF₂),5.78 (1H, ddd, J=56.17, 56.06 and 4.82 Hz, CHF₂); δ_(C) (125 MHz, CDCl₃)−5.182/−4.845 (Si(CH₃)₂), 18.362/18.410 (SiC(CH₃)₃), 25.793/25.826(SiC(CH₃)₃), 51.512/51.670 and 51.829 (CHCHF₂), 68.275/68.314(CH₂CHOTBDMS), 72.588 (CH₂CHCHF₂), 73.741 (CHOTBDMS),82.441/82.483/82.523 and 82.585 (CHCHCHOTBDMS), 113.622/115.547 and117.471 (CHF₂).

(iii) Preparation of(3R,3aS,6R,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (100a)

Tetrabutylammonium fluoride solution (1.0M in tetrahydrofuran, 1.38 mL,1.38 mmol) was added to a stirred solution of (98a) (369 mg, 1.26 mmol)in tetrahydrofuran (1.5 mL). The solution was stirred for 40 minutesthen dichloromethane (15 mL) was added. The solution was dried (Na₂SO₄),filtered and the majority of solvents removed in vacuo to leave alcohol(99a) which was used without further purification. HPLC-MS 181.0 [M+H]⁺.

Pyridine (2.25 mL) then p-toluenesulfonyl chloride (956 mg, 5.02 mmol)were added to alcohol (99a) (prepared as above, assumed to be 1.26mmol). The mixture was stirred under an atmosphere of argon for 20 hoursthen diluted with water (25 mL). The product was extracted intotert-butyl methyl ether (2×15 mL) then dried (Na₂SO₄), filtered andreduced in vacuo to leave an orange oil (524 mg). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 0:100 to 30:70gave tosylate (100a) as a white solid (306 mg, 73%). TLC(R_(f)=0.45,EtOAc:heptane 2:3), analytical HPLC main peak, R_(t)=13.987 min; HPLC-MS335.1 [M+H]⁺, 352.1, 357.1 [M+Na]⁺, 691.1 [2M+Na]⁺, [α]_(D) ²² +90.7°(c=2.15, CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (3H, s, aryl-CH₃),2.63-2.74 (1H, m, CHCHF₂), 3.78 (1H, brt, J=10.02 Hz, 1×CH₂CHCHF₂), 3.85(2H, d, J=5.81 Hz, CH₂CHOTs), 4.02 (1H, t, J=8.57 Hz, 1×CH₂CHCHF₂), 4.57(1H, t, J=4.64 Hz, CHCHCHF₂), 4.60 (1H, t, J=4.79 Hz CHCHOTs), 4.91 (1H,dd, J=10.99 and 5.71 Hz, CHOTs), 5.95 (1H, ddd, J=55.92, 55.23 and 7.32Hz, CHF₂), 7.34 (2H, brdd, J=8.56 and 0.60 Hz, aromatic CH₃CCH), 7.82(2H, brd, J=8.33 Hz, aromatic OSO₂CCH); δ_(C) (125 MHz, CDCl₃) 21.680(aryl-CH₃), 49.136/49.315 and 49.493 (CHCHF₂), 68.625/68.698(CH₂CHCHF₂), 70.936 (CH₂CHOTs), 78.612 (CHOTs), 81.999/82.072(CHCHCHF₂), 82.301 (CHCHOTs), 113.808/115.693/115.721 and 117.605(CHF₂), 127.952 and 129.882 (aromatic CH), 133.192 (CHOSO₂C quaternary),145.209 (CH₃C quaternary).

(iv) Preparation of (R)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropylmethanesulfonate (102a)

A stirred mixture of lithium bromide (3.17 g, 36.41 mmol) and tosylate(100a) (3.04 g, 9.10 mmol) in dimethylformamide (25 mL) was heated at120° C. for 3.5 hours under an atmosphere of argon then diluted withwater (300 mL). The product was extracted into tert-butyl methyl ether(2×250 mL) then the combined organic layers washed with water (5×200mL), brine (200 mL), dried (Na₂SO₄), filtered and partially reduced invacuo to leave bromide (101a) as a brown oil (2.08 g) which was usedwithout further purification.

A solution of ammonium chloride (595 mg, 11.13 mmol) in water (7.5 mL)was added to a stirred solution of bromide (101a) (prepared as above,assumed to be 8.56 mmol) in tetrahydrofuran (30 mL) followed by zincdust (1.11 g, 17.12 mmol). The mixture was stirred for 17.75 hours thenfiltered through celite in vacuo. The filter cake was washed withdiethyl ether (250 mL) then the filtrate washed with a mixture ofbrine:1M hydrochloric acid (1:1, 150 mL). The aqueous layer wasre-extracted with diethyl ether (150 mL) then the combined organiclayers were washed with brine (100 mL), then dried (MgSO₄), filtered andthe majority of solvents removed in vacuo to leave a yellow oil whichwas dissolved in dichloromethane (22.5 mL) then cooled to 0° C.

Triethylamine (4.17 mL, 30.0 mmol) then methanesulfonyl chloride (2.32mL, 30.0 mmol) were added then the suspension stirred for 40 minutes at0° C., then at ambient temperature for 35 minutes. Dichloromethane (200mL) was added then the mixture washed with water (75 mL), brine (75 mL),dried (Na₂SO₄), filtered and reduced in vacuo to leave a residue (2.92g). Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 35:65 gave mesylate (102a) as a pale brown oil (1.674g, 76%). TLC (R_(f)=0.32, EtOAc:heptane 2:3); HPLC-MS 243.0 [M+H]⁺,265.0 [M+Na]⁺; [α]_(D) ²² −40.00° (c=2.00, CHCl₃); δ_(H) (500 MHz,CDCl₃) 2.35-2.45 (1H, m, CHCHF₂), 3.01 (3H, s, OSO₂CH₃), 4.39 (2H, d,J=5.22 CH₂OMs), 4.59-4.69 (2H, m, OCH₂CH═CH), 5.06-5.11 (1H, m,OCHCH═CH), 5.83-5.87 and 6.02-6.05 (2H total, m, CH═CH), 5.97 (1H, dt,J=55.54 and 4.65 Hz, CHF₂); δ_(C) (125 MHz, CDCl₃) 37.217 (OSO₂CH₃),47.589/47.740 and 47.890 (CHCHF₂), 64.770/64.818 and 64.858 (CH₂OMs),75.679 (OCH₂CH—CH), 81.545/81.582 and 81.618 (OCHCH═CH), 113.674/115.606and 117.538 (CHF₂), 126.730 and 128.685 (CH═CH).

(v) Preparation of benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropyl carbamate (104a)

A stirred mixture of mesylate (102a) (1.67 g, 6.90 mmol), ammoniumhydroxide (10 mL) and ammonia in propan-2-ol (2M, 5 mL, 10 mmol) washeated at 70° C. in a sealed tube for 6 hours then stirred at ambienttemperature for 16 hours, then heated at 70° C. for 8 hours. Themajority of the solvents were removed in vacuo then the residue wasazeotroped with diethyl ether (3×10 mL) to obtain amine (103a) which wasused without further purification.

1,4-Dioxan (7.5 mL) then a solution of sodium carbonate (1.83 g, 17.25mmol) in water (6.5 mL) was added whilst stirring to the crude amine(103a) (prepared as above, assumed to be 6.90 mmol) followed bybenzylchloroformate (2.17 mL, 15.18 mmol) over 5 minutes. The mixturewas stirred for 65 minutes before adding dichloromethane (30 mL) andwater (40 mL). The organic phase was separated and the aqueousre-extracted with dichloromethane (2×15 mL). The combined organic layerswere washed with brine (20 mL), then dried (Na₂SO₄), filtered andreduced in vacuo to leave a brown oil (2.82 g). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 0:100 to 30:70gave benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropylcarbamate (104a) asa colourless oil that contained other components (1.83 g, approximately85% purity, 76%). TLC (R_(f)=0.45, EtOAc:heptane 2:3), analytical HPLCmain peak, R_(f)=13.020 min; HPLC-MS 298.1 [M+H]⁺, 320.1 [M+Na]⁺, 617.2[2M+Na]⁺, [α]_(D) ²² −45.1° (c=2.108, CHCl₃); δ_(H) (500 MHz, CDCl₃)2.13-2.26 (1H, m, CHCHF₂), 3.29-3.36 and 3.49-3.57 (2H total, m, CH₂NH),4.58-4.67 (2H, m, CH₂CH═CH), 4.69 (1H, d, J=5.95 Hz, CHCH═CH), 5.03-5.17(3H, m, NH and CH₂Ph), 5.82-6.04 (2H total, m, CH═CH), 5.91 (1H, dt,J=55.89 and 4.84 Hz, CHF₂), 7.28-7.37 (5H, m, aromatic-CH); δ_(C) (125MHz, CDCl₃) 36.545/36.584 and 36.621 (CH₂NH), 47.678/47.819 and 47.958(CHCHF₂), 66.799 (CH₂Ph), 75.658 (OCH₂CH═CH), 83.362/83.402 and 83.442(OCHCH═CH), 115.273/117.202 and 119.131 (CHF₂), 126.964, 127.193,128.122, 128.157, 128.235, 128.518 and 128.544 (CH═CH and aromatic CH),136.403 (Cbz quaternary), 156.321 (Cbz C═O).

(vi) Preparation of benzyl(R)-2-((1R,2R,55)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-3,3-difluoropropylcarbamate(105a)

To a solution of benzyl(R)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropylcarbamate (104a)(1.79 g, 6.03 mmol) in acetonitrile (36 mL) and aqueous Na₂.EDTA (0.4mmol solution, 36 mL) at 0° C. was added 1,1,1-trifluoroacetone (6.47mL, 72.3 mmol). To this solution was added in portions a mixture ofsodium bicarbonate (4.25 g, 50.6 mmol) and OXONE® (11.49 g, 18.7 mmol)over a period of 1 hour. The mixture was stirred for 25 minutes thendiluted with water (250 mL) and the product extracted intodichloromethane (2×150 mL). The combined organic layers were washedconsecutively with water (150 mL), aqueous sodium hydrogen sulphitesolution (5%, 150 mL) and water (100 mL), then dried (Na₂SO₄), filteredand reduced in vacuo to leave a colourless oil (1.62 g). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures0:100 to 40:60 gave a mixture of anti-(105a) and syn-(105a)(approximately 4:1 respectively) as a colourless oil (1.11 g, 59%). Datafor anti-(105a); TLC (R_(f)=0.30, EtOAc:heptane 40:60), analytical HPLCmain peak, R_(t)=10.940 min., HPLC-MS 314.1 [M+H]⁺, 336.1 [M+Na]⁺, 649.2[2M+Na]⁺; δ_(H) (500 MHz, CDCl₃) 2.13-2.27 (1H, m, CHCHF₂), 3.30 (1H,dt, J=14.49 and 6.05 Hz, 1×CH₂NH), 3.50-3.61 (1H, m, 1×CH₂NH), 3.73 (1H,d, J=10.54 Hz, 1×OCH₂CH), 3.79-3.83 and 3.85-3.89 (2H total, m,OCH₂CHCH), 3.99 (1H, d, J=10.59 Hz, 1×OCH₂CH), 4.25 (1H, d, J=7.38 Hz,OCHCHCHF₂), 5.05-5.13 (2H, m, CH₂Ph), 5.13 (1H brs, NH), 5.91 (1H, dt,J=55.58 and 3.93 Hz, CHF₂), 7.30-7.38 (5H, m, aromatic CH); δ_(C) (125MHz, CDCl₃) 37.341/37.383 and 37.423 (CH₂NHCbz), 45.038/45.183 and45.328 (CHCHF₂), 56.416 and 58.186 (OCH₂CHCH), 66.982 (CH₂Ph), 67.278(OCH₂CH), 75.000/75.032 and 75.063 (OCHCHCHF₂), 114.827/116.760 and118.693 (CHF₂), 128.122, 128.270, 128.414, 128.440, 128.506 and 128.565(aromatic CH), 136.193 (Cbz quaternary), 156.435 (Cbz C═O).

(vii) Preparation of (3R,3aR,6R,6aR)-benzyl 6-(difluoromethyl)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (106a)

Sodium hydride (60% dispersion in oil, 169 mg, 4.23 mmol) was added over2 minutes to a solution of a mixture of epoxides (105a) (1.06 g, 3.39mmol) in tetrahydrofuran (12 mL) at 0° C. The mixture was stirred for 30minutes at 0° C. then at ambient temperature for 45 minutes.Dichloromethane (200 mL) was added then the solution was washed withbrine (100 mL) dried (Na₂SO₄), filtered and reduced in vacuo to leave apale brown residue (1.16 g). Flash chromatography over silica, elutingwith ethyl acetate:heptane mixtures 20:80 to 50:50 gave bicyclic alcohol(106a) as a colourless oil (0.57 g, 54%). TLC (R_(f)=0.34, EtOAc:heptane1:1), analytical HPLC single main peak, R_(t)=11.545 min., HPLC-MS 314.1[M+H]⁺, 336.1 [M+Na]⁺, 649.2 [2M+Na]⁺, [α]_(D) ²²−48.5° (c=2.474,CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 2:1;2.55-2.66 (1H, m, CHCHF₂), 3.18-3.27 (1H, m, 1×CbzNCH₂), 3.76-3.83(1.66H, m, 1×CbzNCH₂ major and 1×OCH₂CHOH), 3.88-3.94 (0.66H, m,1×CbzNCH₂ minor and 1×OCH₂CHOH minor), 3.95-4.01 (0.66H, m, 1×OCH₂CHOHmajor), 4.24 (0.66H, brs, CbzNCH major), 4.25 (0.33H, brs, CbzNCHminor), 4.38 (0.33H, brs, OCH₂CHOH minor), 4.49 (0.66H, brs, OCH₂CHOHmajor), 4.74 (0.66H, brt, J=4.28 Hz, CHCHCHF₂ major), 4.77 (0.33H, brt,J=4.17 Hz, CHCHCHF₂ minor), 5.08-5.22 (2H, m, CH₂Ph), 5.82-6.08 (1H, m,CHF₂), 7.31-7.39 (5H, m, aromatic CH); δ_(C) (125 MHz, CDCl₃)45.023/45.103 and 45.381/45.463 (CbzNCH₂), 46.412/46.593 and46.794/46.975/47.155 (CHCHF₂), 67.543 (CH₂Ph), 70.112/71.220 (CbzNCH),75.039/75.138 (OCH₂CHOH), 75.494/76.488 (OCH₂CHOH), 80.219/80.290 and81.190/81.262 (CHCHCHF₂), 114.347/116.240/118.145 and114.408/116.305/118.203 (CHF₂), 128.052, 128.262, 128.343, 128.413,128.508, 128.603 and 128.727 (aromatic CH), 135.931/136.113 (Cbzquaternary), 154.006/154.709 (Cbz C═O).

(viii) Preparation of (3R,3aR,6R,6aR)-(9H-fluoren-9-yl)methyl6-(difluoromethyl)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c; R²═CHF₃)

Methanol (4 mL) was added dropwise to a mixture of 10% palladium oncharcoal (30 mg) and bicyclic alcohol (106a) (250 mg, 0.80 mmol) underan atmosphere of argon at 0° C. The argon was replaced by hydrogen thenthe suspension was stirred at ambient temperature for 50 minutes thenfiltered through celite in vacuo. The filter cake was washed withethanol (30 mL) then the solvents removed in vacuo from the filtrate.The residue was azeotroped with diethyl ether (3×10 mL) to obtain thecrude(3R,3aR,6R,6aR)-6-(difluoromethyl)hexahydro-2H-furo[3,2-b]pyrrol-3-olwhich was used without further purification.

A solution of sodium carbonate (186 mg, 1.76 mmol) in water (1.5 mL) wasadded whilst stirring to a solution of(3R,3aR,6R,6aR)-6-(difluoromethyl)hexahydro-2H-furo[3,2-b]pyrrol-3-ol(prepared as above, assumed to be 0.80 mmol) in 1,4-dioxan (1.5 mL). Asolution of 9-fluorenylmethoxycarbonyl chloride (227 mg, 0.88 mmol) in1,4-dioxan (1.5 mL) was added then the mixture stirred for 65 minutesthen dichloromethane (20 mL) was added and the mixture washed with water(20 mL). The aqueous layer was re-extracted with dichloromethane (2×10mL) then the combined organic layers dried (Na₂SO₄), filtered andreduced in vacuo to leave a colourless oil (530 mg). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures15:85 to 50:50 gave alcohol (2c: R²═CHF₂) (296 mg, 93%) as a whitesolid. TLC (R_(f)=0.35, EtOAc:heptane 1:1), analytical HPLC single mainpeak, R_(t)=15.861 min., HPLC-MS 402.2 [M+H]⁺, 424.1 [M+Na]⁺; [α]_(D) ²²−31.1° (c=1.93, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamersmajor:minor 3:2; 1.08 (0.6H, d, J=3.97 Hz, OH major), 2.34-2.44 (0.6H,m, CHCHF₂ major), 2.52-2.64 (0.4H, m, 2.59 CHCHF₂ minor), 2.94 (0.4H, d,J=3.45 Hz, OH minor), 3.01 (0.6H, brt, J=11.19 Hz, 1×FmocNCH₂ major),3.16 (0.4H, brt, J=11.03 Hz, 1×FmocNCH₂ minor), 3.45 (0.6H, d, J=4.44Hz, FmocNCH major), 3.45-3.49 (0.6H, m, OCH₂CHOH major), 3.51 (0.6H, dd,J=10.06 and 2.36 Hz, 1×OCH₂CHOH major), 3.65-3.73 (1.6H, m, 1×FmocNCH₂and 1×OCH₂CHOH major), 3.78 (0.4H, dd, J=9.90 and 2.70 Hz, 1×OCH₂CHOHminor), 3.93 (0.4H, dd, J=9.89 and 4.59 Hz, 1×OCH₂CHOH minor), 4.18-4.24(1.4H, m, FmocNCH minor and Fmoc CH), 4.39-4.42 (0.4H, m, OCH₂CHOHminor), 4.42-4.50 (1.4H, m, Fmoc CH₂ minor and OCHCHCHF₂ major), 4.72(0.4H, t, J=4.22 Hz, OCHCHCHF₂ minor), 4.77 (0.6H, dd, J=10.83 and 3.68Hz, 1×Fmoc CH₂ major), 4.83 (0.6H, dd, J=10.84 and 3.95 Hz, 1×Fmoc CH₂major), 5.67-6.08 (1H, m, CHF₂), 7.29-7.81 (8H, Fmoc aromatic CH); δ_(C)(125 MHz, CDCl₃) 74.831/44.903 and 44.980 (FmocNCH₂),46.145/46.323/46.507 and 46.961 (CHCHF₂), 47.260/47.371 (Fmoc CH),65.802/67.564 (Fmoc CH₂), 70.444/71.146 (FmocNCH), 74.723/74.965(OCH₂CHOH), 75.539/76.096 (OCH₂CHOH), 80.147/80.218 and 80.813/80.885(OCHCHCHF₂), 114.312/116.210 and 118.110 (CHF₂), 119.870, 119.904,120.055, 124.418, 124.439, 124.851, 124.877, 127.089, 127.485, 127.514,127.855, 127.945 and 127.953 (Fmoc aromatic CH), 141.221, 141.352,141.371, 141.451, 143.548, 143.657, 143.882 and 143.888 (Fmocquaternary), 153.765/154.652 (Fmoc C═O).

(ix) Preparation of(3aS,6R,6aR)-(9H-fluoren-9-yl)methyl-6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d: R²═CHF₂)

Dess-Martin periodinane (539 mg, 1.27 mmol) was added to a stirredsolution of alcohol (2c: R²═CHF₂) (255 mg, 0.64 mmol) in dichloromethane(5 mL) under an atmosphere of argon. The mixture was stirred for 22hours then diluted with dichloromethane (20 mL). The organic phase waswashed with a mixture of saturated aqueous sodium bicarbonate and 0.25Msodium thiosulphate solution (1:1, 10 mL), then saturated aqueous sodiumbicarbonate (10 mL), then brine (10 mL), then dried (Na₂SO₄), filteredand reduced in vacuo. Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 15:85 to 35:65 gave ketone (2d: R²═CHF₂)(230 mg, 91%) as a white solid. TLC (R_(f)=0.38, EtOAc:heptane 1:1),analytical HPLC broad main peak, R_(t)=15.245 min., HPLC-MS 400.1[M+H]⁺, 422.1 [M+Na]⁺, 440.1 [M+H₂O+Na]⁺, 821.2 [2M+Na]⁺; [α]_(D) ²²−108.1° (c=1.988, CHCl₃); δ_(C) (125 MHz, CDCl₃); 45.024/45.472(FmocNCH₂), 46.719/46.904/47.132/47.229/47.427 and 47.607 (Fmoc-CH andCHCHF₂), 62.336/62.822 (FmocNCH), 67.881/68.447 (Fmoc-CH₂), 70.718(OCH₂C═O), 80.453/80.523 and 81.449 (OCHCHCHF₂), 113.339/115.233 and117.128 (CHF₂),120.013/120.165/120.294/124.321/124.894/125.091/125.364/127.065/127.118/127.234/127.796/127.872and 128.042 (Fmoc aromatic CH), 141.269, 141.338, 143.498, 143.752 and144.278 (Fmoc quaternary), 154.580 (Fmoc C═O), 206.629/206.708 (ketoneC═O).

Preparation of (3aS,6S,6aR)-(9H-fluoren-9-yl)methyl6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d′: R¹═CHF₂). Following General Schemes 8 and 9 (i) Preparation of(3R,3aS,6S,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yl4-methylbenzenesulfonate (100b)

Tetrabutylammonium fluoride solution (1.0M in tetrahydrofuran, 2.5 mL,2.5 mmol) was added to a stirred solution oftert-butyl((3R,3aS,6S,6aR)-6-(difluoromethyl)hexahydrofuro[3,2-b]furan-3-yloxy)dimethylsilane(98b) (666 mg, 2.26 mmol) in tetrahydrofuran (2.5 mL). The solution wasstirred for 45 minutes then dichloromethane (25 mL) was added. Thesolution was dried (Na₂SO₄), filtered and the majority of solventsremoved in vacuo to leave alcohol (99b) which was used without furtherpurification. HPLC-MS 181.0 [M+H]⁺.

Pyridine (5.0 mL) then p-toluenesulfonyl chloride (1720 mg, 9.04 mmol)were added to alcohol (99b) (prepared as above, assumed to be 2.26mmol). The mixture was stirred under an atmosphere of argon for 20 hoursthen diluted with water (75 mL). The product was extracted intotert-butyl methyl ether (3×50 mL) then dried (Na₂SO₄), filtered andreduced in vacuo to leave an orange oil (680 mg). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 0:100 to 25:75gave tosylate (100b) as a white solid (548 mg, 72.6%). TLC (R_(f)=0.55,EtOAc:heptane 1:1), analytical HPLC main peak, R_(t)=13.16 min.; HPLC-MS335.1 [M+H]⁺, 352.1, [M+Na]⁺, 691.0 [2M+Na]⁺, [α]_(D) ²² +66.25° (c=3.4,CHCl₃); δ_(H) (500 MHz, CDCl₃) 2.44 (3H, s, aryl-CH₃), 2.67-2.77 (1H, m,CHCHF₂), 3.82-3.85 (2H, m, CH₂CHOTs), 3.95-3.98 (1H, m, 1×CH₂CHCHF₂),4.02-4.08 (1H, m, 1×CH₂CHCHF₂), 4.53 (1H, t, J=5.20 Hz, CHCHCHF₂), 4.61(1H, b, CHCHOTs), 4.84 (1H, dd, J=11.20 and 5.70 Hz, CHOTs),5.64/5.76/5.87 (0.25, 0.5, 0.25H, ddd, CHF₂), 7.34 (2H, d, J=8.00,aromatic CH₃CCH), 7.82 (2H, d, J=8.00 Hz, aromatic OSO₂CCH); δ_(C) (125MHz, CDCl₃) 21.68 (aryl-CH₃), 51.17/51.33 and 51.49 (CHCHF₂),68.57/68.61/68.65 (CH₂CHCHF₂), 69.96 (CH₂CHOTs), 78.30 (CHOTs), 81.07(CHCHOTs), 82.56/82.60/82.64 (CHCHCHF₂), 113.11/115.693/115.04/116.97(CHF₂), 127.95/133.19 (aromatic CH), 133.192 (CHOSO₂C quaternary),145.17 (CH₃C quaternary).

(ii) Preparation of (S)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropylmethane sulfonate (102b)

A stirred mixture of lithium bromide (554 mg, 6.38 mmol) and tosylate(100a) (533 mg, 1.59 mmol) in dimethylformamide (4 mL) was heated at115-120° C. for 6 hours under an atmosphere of argon then reduced invacuo to leave a tan solid (˜2.8 g). The residue was partially dissolvedin TBME (10 mL) and extracted with water (5 mL). The organic layer wasdried (Na₂SO₄), filtered and reduced in vacuo to give a mobile tan oilbromide (101b) (384 mg, assuming 1.59 mmol) which was used withoutfurther purification.

A solution of ammonium chloride (111 mg, 2.07 mmol) in water (1.5 mL)was added to a stirred solution of bromide (101b) (prepared as above,assumed to be 1.59 mmol) in tetrahydrofuran (6 mL) followed by zinc dust(207 mg, 3.18 mmol). The mixture was stirred for 20 hours then filteredthrough celite in vacuo. The filter cake was washed with diethyl ether(2×15 mL mL) then the filtrate washed with a mixture of brine:1Mhydrochloric acid (1:1, 15 mL). The combined organic were washed withbrine (15 mL), then dried (MgSO₄), filtered and the majority of solventsremoved in vacuo to leave a tan oil (˜300 mg) which was dissolved indichloromethane (5 mL) then cooled to 0° C.

Triethylamine (0.78 mL, 5.57 mmol) then methanesulfonyl chloride (0.43mL, 5.57 mmol) were added then the suspension stirred for 40 minutes at0° C., then at ambient temperature for 35 minutes. Dichloromethane (20mL) was added then the mixture washed with water (10 mL), brine (10 mL),dried (Na₂SO₄), filtered and reduced in vacuo to leave a residue (0.6g). Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 20:80 gave mesylate (102b) as a clear oil (239 mg,62%). TLC (R_(f)=0.45, EtOAc:heptane 1:1); HPLC-MS 243.1 [M+H]⁺, 265.0[M+Na]⁺; [α]_(D) ²² −62.5° (c=1.76, CHCl₃); δ_(C) (125 MHz, CDCl₃) 37.29(OSO₂CH₃), 47.28/47.43 and 47.57 (CHCHF₂), 64.38/64.41/64.43 and 64.46(CH₂OMs), 75.44 (OCH₂CH═CH), 81.88/81.91/81.92 and 81.95 (OCHCH═CH),113.40/115.33 and 117.27 (CHF₂), 126.22/126.33 and 128.95 (CH═CH).

(iii) Preparation of benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropyl carbamate (104b)

A stirred mixture of mesylate (102b) (239 mg, 0.99 mmol), ammoniumhydroxide (2 mL) and ammonia in propan-2-ol (2M, 1 mL, 2 mmol) washeated at 70° C. in a sealed tube for 6 hours then stirred at ambienttemperature for 16 hours and this cycle repeated for 4 days. Themajority of the solvents were removed in vacuo then the residue wasazeotroped with diethyl ether (3×5 mL) to obtain amine (103b) which wasused without further purification.

1,4-Dioxan (1 mL) then a solution of sodium carbonate (264 mg, 2.5 mmol)in water (1 mL) was added whilst stirring to the crude amine (103b)(prepared as above, assumed to be 0.99 mmol) followed bybenzylchloroformate (0.313 mL, 2.2 mmol) in 1,4-dioxan (1 mL) over 5minutes. The mixture was stirred for 1 hour before addingdichloromethane (10 mL) and water (10 mL). The organic phase wasseparated and the aqueous re-extracted with dichloromethane (10 mL). Thecombined organic layers were washed with brine (10 mL), then dried(Na₂SO₄), filtered and reduced in vacuo to leave a tan oil (0.6 g).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 0:100 to 7.5:92.5 gave benzyl(S)-2-((S)-2,5-dihydrofuran-2-yl)-3,3-difluoropropylcarbamate (104b) asa colourless oil that contained other components (151 mg, approximately85% purity, 50%). TLC (R_(f)=0.56, EtOAc:heptane 1:1), analytical HPLCmain peak, R_(t)=13.38 min; HPLC-MS 298.1 [M+H]⁺, 320.1 [M+Na]⁺, 617.2[2M+Na]⁺, [α]_(D) ²² −63.7° (c=1.57, CHCl₃); δ_(C) (125 MHz, CDCl₃)36.70/36.74 and 36.78 (CH₂NH), 47.44/47.58 and 47.72 (CHCHF₂), 66.82(CH₂Ph), 75.36 (OCH₂CH═CH), 83.41/83.44/83.46 and 83.49 (OCHCH═CH),114.98/116.91 and 118.83 (CHF₂), 126.97, 128.03, 128.11, 128.16, 128.35,128.47 and 128.52 (CH═CH and aromatic CH), 136.39 (Cbz quaternary),156.34 (Cbz C═O).

(iv) Preparation of benzyl(S)-2-((1R,2R,5S)-3,6-dioxabicyclo[3.1.0]hexan-2-yl)-3,3-difluoropropylcarbamate(105b)

To a solution of alkene (104b) (147 mg, 0.49 mmol) in acetonitrile (3.6mL) and aqueous Na₂.EDTA (0.04 mmol solution, 3.6 mL) at 0° C. was added1,1,1-trifluoroacetone (0.53 mL, 5.9 mmol). To this solution was addedin portions a mixture of sodium carbonate (0.352 g, 4.2 mmol) and OXONE®(0.942 g, 1.53 mmol) over a period of 1 hour. The mixture was stirredfor 25 minutes then diluted with water (25 mL) and the product extractedinto dichloromethane (3×25 mL). The combined organic layers were washedconsecutively with water (150 mL), aqueous sodium hydrogen sulphitesolution (5%, 25 mL) and brine (25 mL), then dried (Na₂SO₄), filteredand reduced in vacuo to leave a colourless oil (0.19 g), used withoutfurther purification. HPLC-MS 314.1 [M+H]⁺, 336.1 [M+Na]⁺.

(v) Preparation (3R,3aR,6S,6aR)-benzyl 6-(difluoromethyl)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (106b)

Sodium hydride (60% dispersion in oil, 26 mg, 0.64 mmol) was added over2 minutes to a solution of a mixture of epoxides (105b) (190 mg, ˜0.49mmol) in tetrahydrofuran (3 mL) at 0° C. The mixture was stirred for 10minutes at 0° C. then at ambient temperature for 3 hour. Dichloromethane(25 mL) was added then the solution was washed with brine (25 mL) dried(Na₂SO₄), filtered and reduced in vacuo to leave a yellow oil (0.18 g).Flash chromatography over silica, eluting with ethyl acetate:heptanemixtures 5:95 to 30:70 gave bicyclic alcohol (106b) as an opaque gum(74.2 mg, 48%). TLC (R_(f)=0.48, EtOAc:heptane 2:1), analytical HPLCsingle main peak, R_(t)=10.81 min., HPLC-MS 314.1 [M+H]⁺, 336.1 [M+Na]⁺,649.2 [2M+Na]⁺, [α]_(D) ²² −37.1° (c=7.42, CHCl₃); δ_(C) (125 MHz,CDCl₃) 44.79/45.23 (CbzNCH₂), 47.12/47.27/47.86/48.02 and 48.18(CHCHF₂), 67.45/67.60/67.89 (CH₂Ph), 69.63/70.57 (CbzNCH), 73.95(OCH₂CHOH), 76.63/76.73 (OCH₂CHOH), 80.88/81.79 (CHCHCHF₂),113.28/115.21/115.31 and 117.15 (CHF₂), 127.89, 127.93, 128.25, 128.32,128.43; 128.53, 128.58, 128.71 and 128.78 (aromatic CH), 136.08 (Cbzquaternary), 154.11/154.97 (Cbz C═O).

(vi) Preparation of (3R,3aR,6S,6aR)-(9H-fluoren-9-yl)methyl6-(difluoromethyl)-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′; R¹═CHF₂)

Methanol (2 mL) was added dropwise to a mixture of 10% palladium oncharcoal (25 mg) and alcohol (106b) (69 mg, 0.22 mmol) under anatmosphere of argon at 0° C. The argon was replaced by hydrogen then thesuspension was stirred at ambient temperature for 1 hour then filteredthrough Mite in vacuo. The filter cake was washed with ethanol (3×10 mL)then the solvents removed in vacuo from the filtrate. The residue wasazeotroped with diethyl ether (3×10 mL) to obtain the crude(3R,3aR,6S,6aR)-6-(difluoromethyl)hexahydro-2H-furo[3,2-b]pyrrol-3-olwhich was used without further purification.

A solution of sodium carbonate (40 mg, 0.46 mmol) in water (2 mL) wasadded whilst stirring to a solution of(3R,3aR,6S,6aR)-6-(difluoromethyl)hexahydro-2H-furo[3,2-b]pyrrol-3-ol(prepared as above, assumed to be 0.22 mmol) in 1,4-dioxan (2 mL). Asolution of 9-fluorenylmethoxycarbonyl chloride (62 mg, 0.23 mmol) in1,4-dioxan (1 mL) was added then the mixture stirred for 10 minutes andstirred at ambient temperature for 1 hour. Dichloromethane (25 mL) wasadded and the mixture washed with brine/pH 5.5 HCl (1:1, 20 mL). Theaqueous layer was re-extracted with dichloromethane (2×15 mL) then thecombined organic layers dried (Na₂SO₄), filtered and reduced in vacuo toleave a colourless gum (110 mg). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 10:90 to 30:70 gave alcohol(2c; R¹═CHF₂) (65.2 mg, 74.2%) as a white solid. TLC (R_(f)=0.40,EtOAc:heptane 2:1), analytical HPLC single main peak, R_(t)=15.31 min.,HPLC-MS 402.2 [M+H]⁺, 424.2 [M+Na]⁺; [α]_(D) ²² −36.4° (c=5.9, CHCl₃);δ_(C) (125 MHz, CDCl₃) 44.57/44.78 (FmocNCH₂),46.88/47.04/47.20/47.29/47.50/48.02 (CHCHF₂ and Fmoc 65.65/67.33 (FmocCH₂), 69.63/70.38 (FmocNCH), 73.64/73.93 (OCH₂CHOH), 76.54/76.73(OCH₂CHOH), 80.82/81.41 and 81.45 (OCHCHCHF₂), 113.20, 115.14, 117.07(CHF₂), 119.89, 119.92, 120.02, 124.41, 124.48, 124.89, 127.07, 127.47,127.53, 127.80 and 127.95 (Fmoc aromatic CH), 141.19, 141.35, 141.42,143.53, 143.72, 143.79 and 143.84 (Fmoc quaternary), 153.91/154.78 (FmocC═O).

(vii) Preparation of (3aS,6S,6aR)-(9H-fluoren-9-yl)methyl6-(difluoromethyl)-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d′; R¹═CHF₂)

Dess-Martin periodinane (125 mg, 0.294 mmol) was added to a stirredsolution of alcohol (2c′; R¹═CHF₂) (59 mg, 0.147 mmol) indichloromethane (3 mL) under an atmosphere of argon. The mixture wasstirred for 20 hours then diluted with dichloromethane (20 mL). Theorganic phase was washed with a mixture of saturated aqueous sodiumbicarbonate and 0.25M sodium thiosulphate solution (1:1, 20 mL), thensaturated aqueous sodium bicarbonate (20 nip, then brine (20 mL), thendried (Na₂SO₄), filtered and reduced in vacuo. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 25:75 gaveketone (2d′; R¹═CHF₂) (44 mg, 75%) as a white solid. TLC (R_(f)=0.45,EtOAc:heptane 1:1), analytical HPLC broad main peak, R_(t)=14.7-17.1min., HPLC-MS 222.1, 400.1 [M+H]⁺, 422.1 [M+Na]⁺, 821.2 [2M+Na]⁺;[α]_(D) ²² −125.6° (c=3.9, CHCl₃); δ_(C) (125 MHz, CDCl₃); 44.80/45.34(FmocNCH₂), 47.18/and 48.26 (Fmoc-CH and CHCHF₂), 61.54/61.87 (FmocNCH),67.69/68.07/68.36 (Fmoc-CH₂), 70.05 (OCH₂C═O), 80.41/81.27 (OCHCHCHF₂),102.76 (C(OH)₂, hydrate), 114.20/115.10 and 117.10 (CHF₂),119.94/120.08/124.89/125.15/125.28/127.07/127.10/127.71/127.74 and127.90 (Fmoc aromatic CH), 141.33/143.57 (Fmoc quaternary), 154.68 (FmocC═O), 207.83 (ketone C═O).

Preparation of (3R,3aR,6R,6aR)-Benzyl3-hydroxy-6-ethyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(113)

A solution of ethylmagnesium bromide (3M in diethyl ether, 2 mL, 6 mmol)was added dropwise over 2 minutes to a stirred suspension of copper(I)bromide (428 mg, 2.98 mmol) and lithium chloride (253 mg, 5.96 mmol) intetrahydrofuran (3 mL) at −50° C. The mixture was stirred for 1.5 hoursat ≦−45° C. then(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate hydrochloride (74) (250 mg, 0.745 mmol) wasadded. The mixture was allowed to warm to 10° C. over 3.75 hours thenwater (5 mL) followed by a solution of sodium carbonate (223 mg, 2.10mmol) in water (2.5 mL) were added. The mixture was stirred for 20minutes then benzyl chloroformate (0.262 mL, 1.84 mmol) was added. Themixture was stirred for 50 minutes at 10° C. then water (25 mL) anddichloromethane (20 mL) were added. The mixture was filtered throughcelite then the filter cake washed with water (5 mL) and dichloromethane(10 mL). The organic layer was separated then the aqueous layerextracted with dichloromethane (2×10 mL). The combined organic layerswere washed with brine (10 mL), dried (Na₂SO₄), filtered and reduced invacuo to leave a red-brown oil (323 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 60:40 gavealcohol (113) (117 mg, 54%) as a pale brown oil. TLC (R_(f)=0.30,EtOAc:heptane 2:1), analytical HPLC main peak, R_(t)=15.172 min.,HPLC-MS 292.2 [M+H]⁺, 605.3 [2M+Na]⁺; [α]_(D) ²³ −44.0° (c=1.136,CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 3:2; 0.96(1.8H, t, J=7.46 Hz, CH₃CH₂ major), 0.97 (1.2H, t, J=7.45 Hz, CH₃CH₂minor), 1.41-1.67 (2H, m, CH₃CH₂), 1.93-2.03 (1H, m, CH₃CH₂CH), 2.20(0.4H, brs, OH minor), 2.83-2.91 (1H, m, 1×CbzNCH₂), 2.99 (0.6H, brs, OHmajor), 3.68-3.89 (2.4H, m, 1×CbzNCH₂ and 1.4×OCH₂CHOH), 3.92 (0.611,dd, J=9.82 and 4.74 Hz, 1×OCH₂CHOH major), 4.16-4.19 (1H, m, CbzNCH),4.32 (0.4H, brs, OCH₂CHOH minor), 4.44 (0.6H, m, OCH₂CHOH major),4.57-4.62 (1H, m, CH₃CH₂CHCH), 5.07-5.21 (2H, m, CH₂Ph), 7.29-7.39 (5H,m, Cbz CH); δ_(C) (125 MHz, CDCl₃) 12.408 (CH₃CH₂), 19.958/20.007(CH₃CH₂), 44.750/45.077 (CH₃CH₂CH), 50.095/50.405 (CbzNCH₂),67.113/67.216 (CH₂Ph), 69.996/71.055 (CbzNCH), 74.393/74.561 (OCH₂CHOH),76.339 (OCH₂CHOH), 82.119/83.046 (CH₃CH₂CHCH), 127.941, 127.965,128.125, 128.249, 128.524 and 128.679 (aromatic CH), 136.418 (Cbzquaternary), 154.887 (Cbz C═O).

Preparation of(3R,3aR,6R,6aR)-6-ethylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (114)

Methanol (2.0 mL) was added dropwise to a mixture of 10% palladium oncharcoal (10 mg) and alcohol (113) (105 mg, 0.36 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 75 mins before filtering the mixture throughcelite in vacuo. The filter cake was washed with ethanol (3×10 mL) thenthe solvents removed in vacuo from the filtrate. The residue wasazeotroped with toluene (2×3 mL) to obtain free base which was usedwithout further purification.

Preparation of (3R,3aR,6R,6aR)-(9H-fluoren-9-yl)methyl6-ethyl-3-hydroxytetra hydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c: R²=Et)

A solution of sodium carbonate (80.1 mg, 0.756 mmol) in water (2.0 mL)was added to an ice-cooled and stirred solution of aminoalcohol (114)(assuming 0.36 mmol) in 1,4-dioxan (2.0 mL). A solution of9-fluorenylmethoxycarbonyl chloride (101 mg, 0.378 mmol) in 1,4-dioxan(1.0 mL) was added over 10 mins then the mixture stirred for 1 hour atambient temperature. The mixture was diluted with dichloromethane (20mL) and washed with 0.1N HCl (20 mL) then brine (20 mL). The organiclayer was dried (Na₂SO₄), filtered and reduced in vacuo to leave ayellow oil (237 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 5:95 to 40:60 gave desired alcohol (2c:R²=Et) as a clear gum (Yield 120.0 mg, 0.316 mmol, 87.8%). TLC(R_(f)=0.35, EtOAc:heptane 1:1), analytical HPLC single main peak,R_(t)=18.96 min., HPLC-MS 380.2 [M+H]⁺, 402.2 [M+Na]⁺; [α]_(D) ²² −30.7°(c=5.7, CHCl₃); δ_(C) (125 MHz, CDCl₃) mixture of approximately 1:1rotamers, 12.33/12.41 (CH₂CH₃), 19.90/19.94/22.67 (CH₂CH₃), 44.48/45.06(CHCH₂CH₃), 47.32/47.45 (Fmoc CH), 49.95/49.98 (FmocNCH₂), 65.57/67.28(Fmoc CH₂), 70.24/71.03 (FmocNCH), 74.22/74.35 (OCH₂CHOH), 76.37(OCH₂CHOH), 82.06/82.74 (OCHCHCH₃), 119.87, 119.90, 119.99, 124.44,124.47, 124.95, 124.97, 127.02, 127.04, 127.42, 127.74, 127.75, 127.83and 127.88 (Fmoc aromatic CH), 141.25, 141.34, 141.36, 141.43, 143.77,143.89, 143.98 and 144.05 (Fmoc quaternary), 153.95/154.85 (Fmoc C═O).

Preparation of (3R,3aR,6R,6aR)-(9H-fluoren-9-yl)methyl6-ethyl-3-oxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d:R²=Et)

Dess-Martin periodinane (257 mg, 0.606 mmol) was added to a stirredsolution of alcohol (2c: R²=Et) (115 mg, 0.303 mmol) in dichloromethane(5 mL) under an atmosphere of argon. The mixture was stirred for 4 hoursthen diluted with dichloromethane (20 mL). The organic phase was washedwith a mixture of saturated aqueous sodium bicarbonate and 0.25M sodiumthiosulphate solution (1:1, 20 mL), then a mixture of saturated aqueoussodium bicarbonate and brine (1:1, 20 mL), then dried (Na₂SO₄), filteredand reduced in vacuo. Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 10:90 to 40:60 gave ketone (2d: R²=Et)(108.4 mg, 0.287 mmol, 94.8%) as a white solid. TLC (R_(f)=0.40,EtOAc:heptane 1:1), analytical HPLC broad main peak, R_(t)=18.50-21.09min., HPLC-MS 378.2 [M+H]⁺, 400.2 [M+Na]⁺, 418.2 [M+H₂O+Na]⁺, 777.2[2M+Na]⁺; [α]_(D) ²² −130.0° (c=1.0, CHCl₃); δ_(H) (500 MHz, CDCl₃)mixture of rotamers 1:1; 1.01 (3H, t, J=7.45 Hz, CH₃CH₂), 1.50-1.70 (2H,b, CH₃CH₂), 2.09 (1H, m, CH₃CH₂CH), 3.08 (1H, q, J=11.20 Hz,1×FmocNCH₂), 3.77 (0.5H, brt, 0.5×FmocNCH₂), 3.90-4.00 (1.5H, m,0.5×FmocNCH₂ and 1×OCH₂C═O), 4.15-4.58 (5H, m, 1×OCH₂C═O, FmocNCH,Fmoc-CH₂ and Fmoc-CH), 4.72/4.77 (1H, brs, 2×0.5 OCHCHCH₂CH₃), 7.30-7.79(8H, Fmoc aromatic CH); δ_(C) (125 MHz, CDCl₃); 12.40 (CH₃CH₂), 18.87(CH₃CH₂), 45.12/45.61 (CH₃CH₂CH), 47.19/47.29 (Fmoc-CH), 49.91/50.24(FmocNCH₂), 62.59/63.05 (FmocNCH), 67.57/68.23 (Fmoc-CH₂), 70.96(OCH₂C═O), 82.21/83.20 (OCHCHCH₂CH₃),119.88/119.94/120.04/124.98/125.16/125.49/127.05/127.69 and 127.77 (Fmocaromatic CH), 141.24, 141.32, 143.66, 143.76, 144.01 and 144.50 (Fmocquaternary), 154.85 (Fmoc C═O), 208.69/208.82 (ketone C═O).

Preparation of (3R,3aR,6S,6aR)-Benzyl6-ethyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(115)

A solution of ethylmagnesium bromide (3M in diethyl ether, 1.51 mL, 4.52mmol) was added dropwise over 4 minutes to a stirred suspension ofcopper(I) bromide (324 mg, 2.26 mmol) and lithium chloride (191 mg, 4.52mmol) in tetrahydrofuran (2.25 mL) at −50° C. The mixture was stirredfor 1.5 hours at ≦−45° C. then(3R,3aR,6S,6aS)-6-bromohexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride(112) (138 mg, 0.564 mmol) was added. The mixture was allowed to warm to0° C. over 2.75 hours then a solution of sodium carbonate (169 mg, 1.59mmol) in water (3.75 mL) was added. The mixture was stirred for 20minutes then benzyl chloroformate (0.198 mL, 1.39 mmol) was added. Themixture was stirred for 1.25 hours at ≦10° C. then water (20 mL) anddichloromethane (15 mL) were added. The mixture was filtered through °elite then the filter cake washed with dichloromethane (15 mL). Theorganic layer was separated then the aqueous layer extracted withdichloromethane (2×10 mL). The combined organic layers were washed withbrine (10 mL), dried (Na₂SO₄), filtered and reduced in vacuo to leave anoily residue (289 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 10:90 to 40:60 gave alcohol (115) (62 mg,38%) as a colourless oil. TLC (R_(f)=0.30, EtOAc:heptane 2:1),analytical HPLC main peak, R_(t)=14.752 min., HPLC-MS 292.2 [M+H]⁺,605.3 [2M+Na]⁺; [α]_(D) ²³ −49.5° (c=0.707, CHCl₃); δ_(H) (500 MHz,CDCl₃) mixture of rotamers major:minor 2:1; 0.91-0.96 (3H, m, CH₃CH₂),1.15-1.39 (2H, m, CH₃CH₂), 2.05 (0.33H, d, J=4.02 Hz, OH minor),2.07-2.14 (1H, m, CH₃CH₂CH), 2.98 (0.66H, d, J=2.99 Hz, OH major),3.34-3.95 (4H, m, CbzNCH₂ and OCH₂CHOH), 3.98-4.04 (1H, m, CbzNCH),4.30-4.34 (0.33H, m, OCH₂CHOH minor), 4.40-4.45 (1.66H, m, CH₃CH₂CHCHand OCH₂CHOH major), 5.08-5.25 (2H, m, CH₂Ph), 7.30-7.38 (5H, m, CbzCH); δ_(C) (125 MHz, CDCl₃) 11.972 (CH₃CH₂), 24.415/24.473 (CH₃CH₂),44.784/45.425 (CH₃CH₂CH), 50.076 (CbzNCH₂), 67.135/67.334 (CH₂Ph),68.554/69.637 (CbzNCH), 73.971 (OCH₂CHOH), 76.524/77.198 (OCH₂CHOH),86.110/87.015 (CH₃CH₂CHCH), 127.766, 127.944, 128.104, 128.316, 128.530and 128.734 (aromatic CH), 136.370/136.418 (Cbz quaternary),154.552/155.520 (Cbz C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-Fluoren-9-yl)methyl6-ethyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′: R¹=Et)

Methanol (0.6 mL) was added dropwise to a mixture of 10% palladium oncharcoal (26 mg) and alcohol (115) (55 mg, 0.189 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1.5 hours then filtered through celite invacuo. The filter cake was washed with ethanol (8 mL) then the solventsremoved in vacuo from the filtrate. The residue was azeotroped withdiethyl ether (3×2 mL) to obtain the crude aminoalcohol (116) which wasused without further purification.

A solution of sodium carbonate (42 mg, 0.397 mmol) in water (0.5 mL) wasadded whilst stirring to a solution of aminoalcohol (116) (assumed to be0.189 mmol) in 1,4-dioxan (0.2 mL). A solution of9-fluorenylmethoxycarbonyl chloride (51 mg, 0.199 mmol) in 1,4-dioxan(0.3 mL) was added then the mixture stirred for 50 minutes thendichloromethane (10 mL) was added and the mixture washed with water (10mL). The aqueous layer was reextracted with dichloromethane (2×5 mL)then the combined organic layers dried (Na₂SO₄), filtered and reduced invacuo to leave a pale yellow oil (107 mg). Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 50:50 gavealcohol (2c′: R¹=Et) (60 mg, 84%) as a colourless oil. TLC (R_(f)-0.38,EtOAc:heptane 2:1), analytical HPLC single main peak, R_(t)=18.651 min.,HPLC-MS 380.2 [M+H]⁺, 402.2 [M+Na]⁺, 781.3 [2M+Na]⁺; [α]_(D) ²² −23.9°(c=0.628, CHCl₃); δ_(C) (125 MHz, CDCl₃) 11.843/11.991 (CH₂CH₃),24.143/24.396 (CH₂CH₃), 44.409/45.428 (CHCH₂CH₃), 47.318/47.596 (FmocCH), 49.564/49.787 (FmocNCH₂), 65.452/67.096 (Fmoc CH₂), 68.641/69.452(FmocNCH), 73.657/73.958 (OCH₂CHOH), 76.469/76.746 (OCH₂CHOH),86.056/86.593 (OCHCHCH₂CH₃), 119.897, 119.916, 120.002, 124.437,124.491, 124.923, 126.997, 127.010, 127.406, 127.431, 127.731, 127.747,127.851 and 127.896 (Fmoc aromatic CH), 141.253, 141.354, 141.378,141.424, 143.752, 143.804, 143.925 and 143.997 (Fmoc quaternary),154.405/155.366 (Fmoc C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-fluoren-9-yl)methyl6-ethyl-3-oxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d′:R¹=Et)

Dess-Martin periodinane (120 mg, 0.284 mmol) was added to a stirredsolution of alcohol (2c′: R¹=Et) (54 mg, 0.142 mmol) in dichloromethane(4 mL) under an atmosphere of argon. The mixture was stirred for 2 hoursthen diluted with dichloromethane (20 mL). The organic phase was washedwith a mixture of saturated aqueous sodium bicarbonate and 0.25M sodiumthiosulphate solution (1:1, 20 mL), then a mixture of saturated aqueoussodium bicarbonate and brine (1:1, 20 mL), then dried (Na₂SO₄), filteredand reduced in vacuo. Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 10:90 to 40:60 gave ketone (2d′: R¹=Et)(44.2 mg, 0.117 mmol, 82.4%) as a clear gum. TLC (R_(f)=0.35,EtOAc:heptane 1:1), analytical HPLC broad main peak, R_(t)=18.20-20.65min., HPLC-MS 378.2 [M+H]⁺, 400.2 [M+Na]⁺, 777.2 [2M+Na]⁺; [α]_(D) ²²−127.5° (c=1.0, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers 1:1;0.90-1.02 (3H, bm, CH₃CH₂), 1.51-1.70 (2H, b, CH₃CH₂), 2.15-2.21 (1H, m,CH₃CH₂CH), 3.35-3.40/3.48-3.61 (1.5H, 1.5×FmocNCH₂), 3.93-3.99 (1H, t,OCH₂C═O), 4.11-4.32 (3.5H, m, 1×OCH₂C═O, 0.5×FmocNCH₂ and 2×Fmoc-CH₂),4.42-4.62 (3H, m, Fmoc-CH, OCHCHCH₂CH₃ and FmocNCH), 7.28-7.78 (8H, Fmocaromatic CH); δ_(C) (125 MHz, CDCl₃); 11.85/11.95 (CH₃CH₂), 23.72(CH₃CH₂), 44.66/45.44 (CH₃CH₂CH), 47.27 (Fmoc-CH), 49.81/50.20(FmocNCH₂), 61.02/61.39 (FmocNCH), 67.39/68.04 (Fmoc-CH₂), 70.05/70.24(OCH₂C═O), 85.59/86.44 (OCHCHCH₂CH₃),119.95/124.91/125.18/125.39/127.02/127.04/127.68 and 127.82 (Fmocaromatic CH), 141.33/143.69 and 143.98 (Fmoc quaternary), 154.20 (FmocC═O), 208.69/209.28 (ketone C═O).

Preparation of (3R,3aR,6R,6aR)-Benzyl3-hydroxy-6-isopropyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(117)

A solution of isopropylmagnesium bromide (2M in diethyl ether, 2.4 mL,4.77 mmol) was added dropwise over 2 minutes to a stirred suspension ofcopper(I) bromide (342 mg, 2.38 mmol) and lithium chloride (202 mg, 4.77mmol) in tetrahydrofuran (2.5 mL) at −50° C. The mixture was stirred for1.5 hours at ≦−45° C. then(3R,3aR,6R,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl4-methylbenzenesulfonate hydrochloride (74) (200 mg, 0.596 mmol) wasadded. The mixture was allowed to warm to 8° C. over 3.25 hours then asolution of sodium carbonate (178 mg, 1.68 mmol) in water (6 mL) wasadded. The mixture was stirred for 20 minutes then benzyl chloroformate(0.21 mL, 1.47 mmol) was added over 1 minute. The mixture was stirredfor 65 minutes at 10° C. then water (20 mL) and dichloromethane (15 mL)were added. The mixture was filtered through celite then the filter cakewashed with dichloromethane (10 mL). The organic layer was separatedthen the aqueous layer extracted with dichloromethane (2×5 mL). Thecombined organic layers were washed with brine (5 mL), dried (Na₂SO₄),filtered and reduced in vacuo to leave a pale pink oil (227 mg). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures10:90 to 55:45 gave alcohol (117) (36 mg, 20%) as a pale brown oil. TLC(R_(f)=0.45, EtOAc:heptane 2:1), analytical HPLC main peak, R_(t)=16.651min., HPLC-MS 306.2 [M+H]⁺, 633.3 [2M+Na]⁺; [α]_(D) ²³ −22.2° (c=0.9,CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers major:minor 3:2; 0.87(1.8H, d, J=6.69 Hz, CH₃CH major), 0.90 (1.2H, d, J=6.71 Hz, CH₃CHminor), 1.13 (1.2H, d, J=6.53 Hz, CH₃CH minor), 1.14 (1.8H, d, J=6.51Hz, CH₃CH major), 1.66 (1H, m, (CH₃)₂CHCH), 1.78-1.88 (1H, m, (CH₃)₂CH),2.06 (0.4H, brs, OH minor), 2.86 (0.6H, brs, OH major), 2.92 (0.4H, t,J=11.09 Hz, 1×CbzNCH₂ minor), 2.94 (0.6H, t, J=11.09 Hz, 1×CbzNCH₂major), 3.68-3.75 (1.6H, m, 1×CbzNCH₂ major and 1×OCH₂CHOH), 3.82-3.88(0.8H, m, 1×CbzNCH₂ minor and 1×OCH₂CHOH minor), 3.93 (0.6H, dd, J=9.83and 4.79 Hz, 1×OCH₂CHOH major), 4.16 (1H, brt, J=161 Hz, CbzNCH), 4.32(0.4H, brs, OCH₂CHOH minor), 4.44 (0.6H, brt, J=3.64 Hz, OCH₂CHOHmajor), 4.41-4.46 (1H, m, (CH₃)₂CHCHCH), 5.08-5.21 (2H, m, CH₂Ph),7.30-7.38 (5H, m, Cbz CH); δ_(C) (125 MHz, CDCl₃) 21.043/21.073 and21.632/21.668 ((CH₃)₂CH), 28.806 ((CH₃)₂CH), 49.494/49.893 (CbzNCH₂),50.708/51.009 ((CH₃)₂CHCH), 67.118/67.239 (CH₂Ph), 70.184/71.253(CbzNCH), 74.301/74.493 (OCH₂CHOH), 76.349/77.246 (OCH₂CHOH),81.734/82.581 ((CH₃)₂CHCHCH), 127.990, 128.138, 128.265, 128.532,128.601 and 128.687 (aromatic CH), 136.439/136.453 (Cbz quaternary),154.196/154.928 (Cbz C═O).

Preparation of (3R,3aR,6R,6aR)-(9H-Fluoren-9-yl)methyl3-hydroxy-6-isopropyl tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c: R²=iPr)

Methanol (0.5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (30 mg) and alcohol (117) (36 mg, 0.118 mmol) under anatmosphere of argon. The argon was replaced by hydrogen then thesuspension was stirred for 1 hour then filtered through celite in vacuo.The filter cake was washed with ethanol (7 mL) then the solvents removedin vacuo from the filtrate. The residue was azeotroped with diethylether (3×2 mL) to obtain the crude aminoalcohol (118) which was usedwithout further purification.

A solution of sodium carbonate (26.3 mg, 0.248 mmol) in water (0.5 mL)was added whilst stirring to a solution of aminoalcohol (118) (assumedto be 0.118 mmol) in 1,4-dioxan (0.2 mL). A solution of9-fluorenylmethoxycarbonyl chloride (32.0 mg, 0.124 mmol) in 1,4-dioxan(0.3 mL) was added then the mixture stirred for 40 minutes thendichloromethane (10 mL) was added and the mixture washed with water (10mL). The aqueous layer was reextracted with dichloromethane (2×5 mL)then the combined organic layers dried (Na₂SO₄), filtered and reduced invacuo to leave a residue (51 mg). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 10:90 to 45:55 gave alcohol(2c: R²=iPr). (31 mg, 67%) as a white solid. TLC (R_(f)=0.52,EtOAc:heptane 2:1), analytical HPLC single main peak, R_(t)=20.046 min.,HPLC-MS 394.2 [M+H]⁺; [α]_(D) ²³ −28.7° (c=1.22, CHCl₃); δ_(C) (125 MHz,CDCl₃) 20.956/21.060 and 21.556/21.653 (CH(CH₃)₂), 26.687/26.783(CH(CH₃)₂), 47.329/47.444 (Fmoc CH), 49.432/49.460 (FmocNCH₂),50.467/51.011 (CHCH(CH₃)₂), 65.624/67.243 (Fmoc CH₂), 70.384/71.110(FmocNCH), 74.206/74.362 (OCH₂CHOH), 76.183/76.723 (OCH₂CHOH),81.673/82.254 (OCHCH(CH₃)₂), 119.864, 119.891, 119.981, 124.448,124.490, 124.951, 127.019, 127.405, 127.414, 127.735, 127.752, 127.832and 127.879 (Fmoc aromatic CH), 141.250, 141.362, 141.376, 141.420,143.798, 143.866, 143.983 and 144.048 (Fmoc quaternary), 154.024/154.860(Fmoc C═O).

Preparation of (3aS,6R,6aR)-(9H-fluoren-9-yl)methyl6-isopropyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d:R²=iPr)

Dess-Martin periodinane (91 mg, 0.214 mmol) was added to a stirredsolution of alcohol (2c: R²=iPr). (42 mg, 0.107 mmol) in dichloromethane(3 mL) under an atmosphere of argon. The mixture was stirred for 2 hoursthen diluted with dichloromethane (20 mL). The organic phase was washedwith a mixture of saturated aqueous sodium bicarbonate and 0.25M sodiumthiosulphate solution (1:1, 20 mL), then a mixture of saturated aqueoussodium bicarbonate and brine (1:1, 20 mL), then dried (Na₂SO₄), filteredand reduced in vacuo. Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 10:90 to 40:60 gave ketone (2d: R²=iPr).(40.4 mg, 0.103 mmol, 96.5%) as a clear gum. TLC (R_(f)=0.45,EtOAc:heptane 1:1), analytical HPLC broad main peak, R_(t)=19.51-22.01min., HPLC-MS 392.2 [M+H]⁺, 414.2 [M+Na]⁺, 805.3 [2M+Na]⁺; [α]_(D) ²²−137.5° (c=1.0, CHCl₃); δ_(H) (500 MHz, CDCl₃) mixture of rotamers 1:1;0.95 (3H, t, (CH₃)₂CH), 1.07 (3H, t, J=6.50 Hz, (CH₃)₂CH), 1.71-1.84(1H, bm, (CH₃)₂CHCH), 1.91-2.20 (1H, m, (CH₃)₂CHCH), 3.07-3.19 (1H, bm,FmocNCH₂), 3.70-3.77 (0.5H, bm, 0.5×FmocNCH₂), 3.90-4.03 ((1.5H, bm,0.5×FmocNCH₂+1×OCH₂C═O), 4.12-4.58 (5H, bm,2×Fmoc-CH₂+Fmoc-CH+OCH₂C═O+FmocNCH), 4.73/4.81 (2×0.5H, bs,OCHCHCH(CH₃)₂), 7.30-7.78 (8H, Fmoc aromatic CH); δ_(C) (125 MHz,CDCl₃); 21.01/21.71 ((CH₃)₂CH), 25.78 ((CH₃)₂CH), 47.18/47.30 (Fmoc-CH),49.41/49.81 (FmocNCH₂), 51.09/51.19/51.53 ((CH₃)₂CHCH), 62.83/63.26(FmocNCH), 67.50/68.25 (Fmoc-CH₂), 70.93 (OCH₂C═O), 81.91/82.84(OCHCHCH(CH₃)₂), 119.88/124.98/125.16/125.50/126.99/127.05/127.63/127.69and 127.81 (Fmoc aromatic CH), 141.23/141.33/143.66/143.73/144.05 and144.52 (Fmoc quaternary), 154.89 (Fmoc C═O), 208.63/208.76 (ketone C═O).

Preparation of (3R,3aR,6S,6aR)-Benzyl3-hydroxy-6-isopropyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(119)

A solution of isopropylmagnesium bromide (2M in diethyl ether, 4.9 mL,9.8 mmol) was added dropwise over 7 minutes to a stirred suspension ofcopper(I) bromide (704 mg, 4.9 mmol) and lithium chloride (416 mg, 9.8mmol) in tetrahydrofuran (5 mL) at −50° C. The mixture was stirred for1.5 hours at ≦−45° C. then(3R,3aR,6S,6aS)-6-bromohexahydro-2H-furo[3,2-b]pyrrol-3-ol hydrochloride(112) (300 mg, 1.23 mmol) was added. The mixture was allowed to warm to0° C. over 2 hours 25 minutes then a solution of sodium carbonate (369mg, 3.48 mmol) in water (8.5 mL) was added over 5 minutes. The mixturewas stirred for 20 minutes then benzyl chloroformate (0.432 mL, 3.03mmol) was added over 1 minute. The mixture was stirred for 1.5 hours at0° C. then at ambient temperature for 40 minutes. Benzyl chloroformate(0.15 mL, 1.05 mmol) was added then the mixture was stirred for 15minutes before adding water (30 ml) and dichloromethane (25 mL). Themixture was filtered through celite then the filter cake washed withdichloromethane (15 mL). The organic layer was separated then theaqueous layer extracted with dichloromethane (2×10 mL). The combinedorganic layers were washed with brine (15 mL), dried (Na₂SO₄), filteredand reduced in vacuo to leave a pale brown oil (755 mg). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures10:90 to 40:60 gave alcohol (119) (130 mg, 35%) as a pale brown oil. TLC(R_(f)=0.50, EtOAc:heptane 2:1), analytical HPLC main peak, R_(t)=16.106min., HPLC-MS 306.2 [M+H]⁺, 633.3 [2M+Na]⁺; [α]_(D) ²¹ −36.1° (c=0.693,CHCl₃); δ_(C) (125 MHz, CDCl₃) 20.187/20.332 and 20.444 ((CH₃)₂CH),29.700/29.909 ((CH₃)₂CH), 49.133/49.355 (CbzNCH₂), 50.689 ((CH₃)₂CHCH),67.187/67.408 (CH₂Ph), 69.553/70.601 (CbzNCH), 73.424/73.629 (OCH₂CHOH),77.081/77.739 (OCH₂CHOH), 85.099/85.973 ((CH₃)₂CHCHCH), 127.830,127.972, 128.145, 128.376, 128.551 and 128.766 (aromatic CH), 136.403(Cbz quaternary), 155.541 (Cbz C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-Fluoren-9-yl)methyl3-hydroxy-6-isopropyl tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′: R¹=iPr)

Methanol (1.25 mL) was added dropwise to a mixture of 10% palladium oncharcoal (40 mg) and alcohol (119) (123 mg, 0.403 mmol) under anatmosphere of argon at 0° C. The argon was replaced by hydrogen then thesuspension was stirred at ambient temperature for 1 hour then filteredthrough celite in vacuo. The filter cake was washed with ethanol (10 mL)then the solvents removed in vacuo from the filtrate. The residue wasazeotroped with diethyl ether (3×2 mL) to obtain the crude aminoalcohol(120) which was used without further purification.

A solution of sodium carbonate (90 mg, 0.847 mmol) in water (1.0 mL) wasadded whilst stirring to a suspension of aminoalcohol (120) (assumed tobe 0.403 mmol) in 1,4-dioxan (0.5 mL). A solution of9-fluorenylmethoxycarbonyl chloride (109 mg, 0.423 mmol) in 1,4-dioxan(0.5 mL) was added then the mixture stirred for 40 minutes thendichloromethane (15 mL) was added and the mixture washed with water (15mL). The organic layer was reextracted with dichloromethane (2×10 mL)then the combined organic layers dried (Na₂SO₄), filtered and reduced invacuo to leave a residue (221 mg). Flash chromatography over silica,eluting with ethyl acetate:heptane mixtures 10:90 to 40:60 gave alcohol(2c′: R¹=iPr) (128 mg, 81%) as a white solid. TLC (R_(f)=0.33,EtOAc:heptane 1:1), analytical HPLC main peak, R_(t)=19.537 min.,HPLC-MS 394.2 [M+H]⁺, 416.2 [M+Na]⁺, 809.3 [2M+Na]⁺; [α]_(D) ²² −27.3°(c=0.732, CHCl₃); δ_(C) (125 MHz, CDCl₃) 20.027/20.228/20.259 and 20.425(CH(CH₃)₂), 29.300/29.753 (CH(CH₃)₂), 47.323/47.633 (Fmoc CH),48.447/49.072 (FmocNCH₂), 48.974/50.612 (CHCH(CH₃)₂), 65.377/67.182(Fmoc CH₂), 69.599/70.383 (FmocNCH), 73.026/73.606 (OCH₂CHOH), 76.987(OCH₂CHOH), 85.013/85.495 (OCHCHCH(CH₃)₂), 119.929, 119.983, 124.388,124.426, 124.866, 124.944, 127.013, 127.045, 127.420, 127.755, 127.865and 127.908 (Fmoc aromatic CH), 141.248, 141.385, 141.419, 143.760,143.828 and 143.987 (Fmoc quaternary), 154.179/155.342 (Fmoc C═O).

Preparation of (3aS,6S,6aR)-(9H-Fluoren-9-yl)methyl 6-isopropyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d′: R¹=iPr)

Dess-Martin periodinane (259 mg, 0.611 mmol) was added to a stirredsolution of alcohol (2c′: R¹=iPr) (120 mg, 0.305 mmol) indichloromethane (4.5 mL) under an atmosphere of argon. The mixture wasstirred for 2 hours 10 minutes then diluted with dichloromethane (20mL). The organic phase was washed with a mixture of saturated aqueoussodium bicarbonate and 0.25M sodium thiosulphate solution (1:1, 20 mL),then saturated aqueous sodium bicarbonate (20 mL), then brine (20 mL),then dried (Na₂SO₄), filtered and reduced in vacuo to leave a colourlessoil (220 mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 40:60 gave ketone (2d′: R¹=iPr) (110mg, 92%) as a colourless oil. TLC (R_(f)=0.70, EtOAc:heptane 2:1),analytical HPLC broad main peak, R_(t)=19.163-21.606 min., HPLC-MS 392.2[M+H]⁺, 414.2 [M+Na]⁺, 432.2 [M+H₂O+Na]⁺, 805.3 [2M+Na]⁺; [α]_(D) ²¹−100.6° (c=0.696, CHCl₃); δ_(H) (500 MHz, CDCl₃) 0.81-1.08 (6H, m,(CH₃)₂CH), 1.62-1.89 (1H, m, (CH₃)₂CH), 1.99-2.06 (1H, m, (CH₃)₂CHCH),3.45-3.61 (1H, m, 1×FmocNCH₂), 3.98 (8H, m, 1×FmocNCH₂, OCH₂C═O,FmocNCH, Fmoc CH₂, Fmoc CH and OCHCHCH(CH₃)₂), 7.28-7.77 (8H, Fmocaromatic CH); δ_(C) (125 MHz, CDCl₃); 20.484 ((CH₃)₂CH), 29.443/29.546((CH₃)₂CH), 47.270 (Fmoc CH), 48.828/49.288 (FmocNCH₂), 48.956/49.982((CH₃)₂CHCH), 61.620/61.967 (FmocNCH), 67.453/67.951 (Fmoc CH₂),69.484/69.615 (OCH₂C═O), 83.997/84.697 (OCHCHCH(CH₃)₂),119.922/119.983/124.898/125.177/125.299/127.036/127.179/127.677 and127.829 (Fmoc aromatic CH), 141.331 and 143.694 (Fmoc quaternary),155.075 (Fmoc C═O), 209.928/210.128 (ketone C═O).

Preparation of (3R,3aR,6S,6aR)-Benzyl3-hydroxy-6-propyltetrahydro-2H-furo[3,2-b]pyrrole-4(5.1)-carboxylate(121)

A solution of n-propylmagnesium chloride (2M in diethyl ether, 5.35 mL,10.7 mmol) was added dropwise over 2 minutes to a stirred suspension ofcopper(I) bromide (768 mg, 5.35 mmol) and lithium chloride (454 mg, 10.7mmol) in tetrahydrofuran (5 mL) at ≦−50° C. The mixture was stirred for1.5 hours at ≦−45° C. then tosylate (85) (400 mg, 1.34 mmol) was added.The mixture was allowed to warm to 5° C. over 4 hours then a solution ofsodium carbonate (400 mg, 3.77 mmol) in water (10 mL) was added. Themixture was stirred for 15 minutes then benzyl chloroformate (0.47 mL,3.29 mmol) was added over 1 minute. The mixture was stirred for 45minutes at ≦10° C. then water (35 mL) and dichloromethane (25 mL) wereadded. The mixture was filtered through celite then the filter cakewashed with dichloromethane (20 mL). The organic layer was separatedthen the aqueous layer extracted with dichloromethane (2×10 mL). Thecombined organic layers were washed with brine (10 mL), dried (Na₂SO₄),filtered and reduced in vacuo to leave an oily residue (720 mg). Flashchromatography over silica, eluting with ethyl acetate:heptane mixtures10:90 to 40:60 gave alcohol (121) (295 mg, 72%) as a colourless oil. TLC(R_(f)=0.30, EtOAc:heptane 2:1), analytical HPLC single main peak,R_(t)=15.984 min., HPLC-MS 306.2 [M+H]⁺, 633.3 [2M+Na]⁺; [α]_(D) ²²−54.6° (c=1.557, CHCl₃); on (500 MHz, CDCl₃) mixture of rotamersmajor:minor 3:2; 0.89 (3H, t, J=7.18 Hz, CH₃CH₂), 1.10-1.40 (4H, m,CH₃CH₂CH₂), 1.82 (0.4H, brs, OH minor), 2.15-2.23 (1H, m, CH₃CH₂CH₂CH),3.09 (0.6H, brs, OH major), 3.33-4.02 (4H, m, CbzNCH₂ and OCH₂CHOH),4.10-4.14 (1H, m, CbzNCH), 4.33 (0.4H, brs, OCH₂CHOH minor), 4.40-4.45(1.6H, m, CH₃CH₂CH₂CHCH and OCH₂CHOH major), 5.08-5.25 (2H, m, CH₂Ph),7.29-7.38 (5H, m, Cbz CH); δ_(C) (125 MHz, CDCl₃) 13.970 (CH₃CH₂),20.592 (CH₃CH₂), 33.569/33.626 (CH₃CH₂CH₂), 42.777/43.424 (CH₃CH₂CH₂CH),50.331 (CbzNCH₂), 67.130/67.331 (CH₂Ph), 68.476/69.547 (CbzNCH), 74.033(OCH₂CHOH), 76.404/77.205 (OCH₂CHOH), 86.343/87.275 (CH₃CH₂CH₂CHCH),127.759, 127.924, 128.097, 128.290, 128.524, and 128.727 (aromatic CH),136.418 (Cbz quaternary), 154.575/155.512 (Cbz C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-Fluoren-9-yl)methyl3-hydroxy-6-propyltetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′: R¹=iPr)

Methanol (4 mL) was added dropwise to a mixture of 10% palladium oncharcoal (50 mg) and alcohol (121) (279 mg, 0.915 mmol) under anatmosphere of argon whilst chilling with iced water. The argon wasreplaced by hydrogen then the suspension was stirred for 1.25 hours. Thehydrogen was replaced by argon then ethanol (4 mL) added beforefiltering through celite in vacuo. The filter cake was washed withethanol (10 mL) then the solvents removed in vacuo from the filtrate.The residue was azeotroped with diethyl ether (3×5 mL) to obtain thecrude aminoalcohol (122) which was used without further purification.

A solution of sodium carbonate (204 mg, 1.92 mmol) in water (2.5 mL) wasadded whilst stirring to a solution of aminoalcohol (122) (assumed to be0.915 mmol) in 1,4-dioxan (1.25 mL). A solution of9-fluorenylmethoxycarbonyl chloride (248 mg, 0.961 mmol) in 1,4-dioxan(1.25 mL) was added over 10 minutes at 0° C. then the mixture stirredfor 35 minutes then dichloromethane (25 mL) was added and the mixturewashed with water (25 mL). The aqueous layer was re-extracted withdichloromethane (2×10 mL) then the combined organic layers dried(Na₂SO₄), filtered and reduced in vacuo to leave a colourless oil (559mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 40:60 gave alcohol (2c′: R¹=n-Pr) (375mg, 104%) as a colourless oil. TLC (R_(f)=0.40, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=19.257 min., HPLC-MS 394.2[M+H]⁺, 416.2 [M+Na]⁺, 809.3 [2M+Na]⁺; [α]_(D) ²² −32.0° (c=1.407,CHCl₃); δ_(C) (125 MHz, CDCl₃) 13.906/14.030 (CH₃CH₂), 20.473/20.611(CH₃CH₂), 33.309/33.570 (CH₃CH₂CH₂), 42.396/43.436 (CH₃CH₂CH₂CH),47.300/47.602 (Fmoc CH), 49.845/50.062 (FmocNCH₂), 65.486/67.103 (FmocCH₂), 68.597/69.368 (FmocNCH), 73.695/74.017 (OCH₂CHOH), 76.374/77.202(OCH₂CHOH), 86.290/86.874 (OCHCHCH₂CH₂CH₃), 119.898, 119.923, 119.996,124.455, 124.514, 124.907, 124.929, 126.996, 127.401, 127.427, 127.745,127.866 and 127.891 (Fmoc aromatic CH), 141.264, 141.354, 141.376,141.422, 143.756, 143.814, 143.929 and 144.011 (Fmoc quaternary),154.420/155.348 (Fmoc C═O).

Preparation of (3aS,6S,6aR)-(9H-Fluoren-9-yl)methyl 6-isopropyl-3-oxotetrahydro-21−/−furo[3,2-b]pyrrole-4(5H)-carboxylate (2d′: R¹=iPr)

Dess-Martin periodinane (777 mg, 1.83 mmol) was added to a stirredsolution of alcohol (2c′: R¹=n-Pr) (360 mg, 0.915 mmol) indichloromethane (15 mL) under an atmosphere of argon. The mixture wasstirred for 3 hours then diluted with dichloromethane (50 mL). Theorganic phase was washed with a mixture of saturated aqueous sodiumbicarbonate and 0.2M sodium thiosulphate solution (1:1, 50 mL), thensaturated aqueous sodium bicarbonate (50 mL), then brine (50 mL), thendried (Na₂SO₄), filtered and reduced in vacuo to leave a residue (533mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 35:65 gave ketone (2d′: R¹=n-Pr) (342mg, 96%) as a colourless oil. TLC (R_(f)=0.70, EtOAc:heptane 2:1),analytical HPLC broad main peak, R_(t)=18.840-21.089 min., HPLC-MS 392.2[M H]⁺, 805.3 [2M+Na]⁺; [α]_(D) ²² −115.1° (c=2.042, CHCl₃); δ_(H) (500MHz, CDCl₃) mixture of rotamers approximately 1:1, 0.93 (3H, t, J=7.22Hz, CH₂CH₂CH₃), 1.07-1.48 (4H, m, CH₂CH₂CH₃), 2.25-2.32 (1H, m,CHCH₂CH₂CH₃), 3.34-3.40 (0.5H, m, 0.5×FmocNCH₂), 3.48-3.60 (1.5H, m,1.5×FmocNCH₂), 3.93-4.02 (1H, m, 1×OCH₂C═O), 4.10-4.34 (3.5H, m,FmocNCH, 0.5×Fmoc CH₂, Fmoc CH and 1×OCH₂C═O), 4.43-4.64 (2.5H, m,1.5×Fmoc CH₂ and OCHCHCH₂CH₂CH₃), 7.28-7.77 (8H, Fmoc aromatic CH);δ_(C) (125 MHz, CDCl₃); 13.978 (CH₂CH₂CH₃), 20.581 (CH₂CH₂CH₃), 32.831(CH₂CH₂CH₃), 42.627/43.413 (OCHCHCH₂), 47.254 (Fmoc CH), 50.107/50.507(FmocNCH₂), 61.017/61.383 (FmocNCH), 67.425/68.074 (Fmoc CH₂),70.141/70.236 (OCH₂C═O), 85.814/86.699 (OCHCHCH₂),119.892/119.952/120.052, 124.903/125.177/125.416/127.011/127.047/127.691and 127.827 (Fmoc aromatic CH), 141.331 and 143.702 (Fmoc quaternary),155.269 (Fmoc C═O), 209.098/209.290 (ketone C═O).

Preparation of (3R,3aR,6S,6aR-Benzyl6-cyclopropyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(123)

A solution of cyclo-propylmagnesium bromide (0.5M in tetrahydrofuran,21.4 mL, 10.7 mmol) was added dropwise over 20 minutes to a stirredsuspension of copper(I) bromide (768 mg, 5.35 mmol) and lithium chloride(454 mg, 10.7 mmol) in tetrahydrofuran (1 mL) at ≦−50° C. The mixturewas stirred for 1.5 hours at ≦−45° C. then tosylate (85) (400 mg, 1.34mmol) was added. The mixture was allowed to warm to 10° C. over 4 hoursthen a solution of sodium carbonate (400 mg, 3.77 mmol) in water (10 mL)was added. The mixture was stirred for 15 minutes then benzylchloroformate (0.47 mL, 3.29 mmol) was added over 1 minute. The mixturewas stirred for 45 minutes at ≦13° C. then water (35 mL) anddichloromethane (25 mL) were added. The mixture was filtered throughcelite then the filter cake washed with dichloromethane (20 mL). Theorganic layer was separated then the aqueous layer extracted withdichloromethane (2×10 mL). The combined organic layers were washed withbrine (10 mL), dried (Na₂SO₄), filtered and reduced in vacuo to leave anoily residue (820 mg). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 10:90 to 40:60 gave alcohol (123) (212mg, 52%) as a pale yellow oil. TLC (R_(f)=0.32, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=14.884 min., HPLC-MS 304.2[M+H]⁺, 629.3 [2M+Na]⁺; [α]_(D) ²² −54.3° (c=1.29, CHCl₃); δ_(H) (500MHz, CDCl₃) mixture of rotamers major:minor 3:2; 0.09-0.17 (1H, m,1×cyclopropyl CH₂), 0.22-0.28 (1H, m, 1×cyclopropyl CH₂), 0.43-0.50 (1H,m, 1×cyclopropyl CH₂), 0.50-0.57 (3H, m, 2×cyclopropyl CH₂ andcyclopropyl CH), 1.51-1.57 (1H, m, CbzNCH₂CH), 2.16 (0.4H, brs, OHminor), 3.02 (0.6H, brs, OH major), 3.37-4.00 (4H, m, CbzNCH₂ andOCH₂CHOH), 4.21-4.25 (1H, m, CbzNCH), 4.34 (0.4H, brs, OCH₂CHOH minor),4.46 (0.6H, m, OCH₂CHOH major), 4.58-4.63 (1H, m, CbzNCH₂CHCHO),5.10-5.26 (2H, m, CH₂Ph), 7.30-7.39 (5H, m, Cbz CH); δ_(C) (125 MHz,CDCl₃) 3.820, 3.870, 4.068 and 4.117 (cyclopropyl CH₂), 12.896(cyclopropyl CH), 48.260/48.860 (CbzNCH₂CH), 50.538 (CbzNCH₂),67.153/67.312 (CH₂Ph), 68.575/69.632 (CbzNCH), 74.087/74.124 (OCH₂CHOH),76.334/77.190 (OCH₂CHOH), 86.256/87.190 (CbzNCH₂CHCHO), 127.780,127.927, 128.097, 128.282, 128.524, and 128.714 (aromatic CH), 136.416(Cbz quaternary), 154.486/155.410 (Cbz C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-Fluoren-9-yl)methyl6-cyclopropyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′: R¹=Cyc-Pr)

Methanol (2.5 mL) was added dropwise to a mixture of 10% palladium oncharcoal (30 mg) and alcohol (123) (199 mg, 0.657 mmol) under anatmosphere of argon whilst chilling with iced water. The argon wasreplaced by hydrogen then the suspension was stirred for 1 hour. Thehydrogen was replaced by argon then ethanol (2.5 mL) added beforefiltering through celite in vacuo. The filter cake was washed withethanol (7.5 mL) then the solvents removed in vacuo from the filtrate.The residue was azeotroped with diethyl ether (3×3 mL) to obtain thecrude aminoalcohol (124) which was used without further purification.

A solution of sodium carbonate (146 mg, 1.38 mmol) in water (2 mL) wasadded whilst stirring to a solution of aminoalcohol (124) (assumed to be0.657 mmol) in 1,4-dioxan (1 mL). A solution of9-fluorenylmethoxycarbonyl chloride (178 mg, 0.690 mmol) in 1,4-dioxan(1 mL) was added over 10 minutes at 0° C. then the mixture stirred for65 minutes then dichloromethane (20 mL) was added and the mixture washedwith water (20 mL). The aqueous layer was re-extracted withdichloromethane (2×5 mL) then the combined organic layers dried(Na₂SO₄), filtered and reduced in vacuo to leave a colourless oil (325mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 40:60 gave alcohol (2c′: R¹=Cyc-Pr)(207 mg, 81%) as a white solid. TLC (R_(f)=0.38, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=18.609 min., HPLC-MS 392.2[M+H]⁺, 414.2 [M+Na]⁺, 805.3 [2M+Na]⁺; [α]_(D) ^(21.5) −36.8° (c=1.767,CHCl₃); δ_(C) (125 MHz, CDCl₃) 3.768, 3.955, 3.880 and 3.768(cyclopropyl CH₂), 12.664/12.867 (cyclopropyl CH), 47.303/47.604 (FmocCH), 47.912/48.819 (FmocNCH₂CH), 50.118/50.334 (FmocNCH₂), 65.541/67.162(Fmoc CH₂), 68.717/69.467 (FmocNCH), 73.838/74.108 (OCH₂CHOH),76251/76.654 (OCH₂CHOH), 86.165/86.807 (FmocNCH₂CHCHO), 119.895,119.920, 120.003, 124.473, 124.528, 124.967, 124.929, 126.993, 127.015,127.385, 127.427, 127.725, 127.750, 127.792 and 127.885 (Fmoc aromaticCH), 141.280, 141.349, 141.379, 141.440, 143.718, 143.852, 143.957 and144.025 (Fmoc quaternary), 154.335/155.241 (Fmoc C═O).

Preparation of (3aS,6S,6aR)-(9H-Fluoren-9-yl)methyl6-cyclopropyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2d′: R¹=Cyc-Pr)

Dess-Martin periodinane (412 mg, 0.972 mmol) was added to a stirredsolution of alcohol (2c′: R¹=Cyc-Pr) (190 mg, 0.486 mmol) indichloromethane (8 mL) under an atmosphere of argon. The mixture wasstirred for 2.5 hours then diluted with dichloromethane (25 mL). Theorganic phase was washed with a mixture of saturated aqueous sodiumbicarbonate and 0.2M sodium thiosulphate solution (1:1, 25 mL), thensaturated aqueous sodium bicarbonate (25 mL), then brine (25 mL), thendried (Na₂SO₄), filtered and reduced in vacuo to leave a residue (306mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 40:60 gave ketone (2c′: R¹=Cyc-Pr)(170 mg, 90%) as a white solid. TLC (R_(f)=0.70, EtOAc:heptane 2:1),analytical HPLC broad main peak, R_(t)=18.02-20.23 min., HPLC-MS 390.2[M+H]⁺, 408.2 [M+H₂O+H]⁺, 412.2 [M+Na]⁺, 430.2 [M+H₂O+Na]⁺, 801.3[2M+Na]⁺; [α]_(D) ²² −95.0° (c=1.00, CHCl₃); δ_(C) (125 MHz, CDCl₃);3.80/3.99 (cyclohexyl CH₂), 12.04/12.09 (cyclohexyl CH), 47.26 (FmocCH), 48.18/48.94 (FmocNCH₂CH), 50.40/50.65 (FmocNCH₂), 61.08/61.52(FmocNCH), 67.48/68.01 (Fmoc CH₂), 70.32/70.39 (OCH₂C═O), 85.97/86.88(FmocNCH₂CHCHO), 119.86, 119.94, 124.94, 124.97, 125.17, 125.41, 127.01and 127.66 (Fmoc aromatic CH), 141.23, 141.33, 143.61, 143.73, 143.93and 144.47 (Fmoc quaternary), 155.08/155.16 (Fmoc C═O), 208.70/208.89(ketone C═O).

Preparation of (3R,3aR,6S,6aR)-Benzyl6-benzyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(125)

A solution of benzylmagnesium chloride (1M in diethyl ether, 10.7 mL,10.7 mmol) was added dropwise over 10 minutes to a stirred suspension ofcopper(I) bromide (768 mg, 5.35 mmol) and lithium chloride (454 mg, 10.7mmol) in tetrahydrofuran (10 mL) at ≦−50° C. The mixture was stirred for1.5 hours at ≦−45° C. then tosylate (85) (400 mg, 1.34 mmol) was added.The mixture was allowed to warm to 8° C. over 4 hours then a solution ofsodium carbonate (400 mg, 3.77 mmol) in water (10 mL) was added over 5minutes. The mixture was stirred for 15 minutes then benzylchloroformate (0.47 mL, 3.29 mmol) was added over 1 minute. The mixturewas stirred for 75 minutes at ≦12° C. then water (35 mL) anddichloromethane (25 mL) were added. The mixture was filtered throughMite then the filter cake washed with dichloromethane (20 mL). Theorganic layer was separated then the aqueous layer extracted withdichloromethane (2×10 mL). The combined organic layers were washed withbrine (10 mL), dried (Na₂SO₄), filtered and reduced in vacuo to leave anoily residue (1.1 g). Flash chromatography over silica, eluting withethyl acetate:heptane mixtures 15:85 to 45:55 gave alcohol (125) (336mg, 71%) as a pale yellow oil. TLC (R_(f)=0.30, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=17.186 min., HPLC-MS 354.2[M+H]⁺, 729.3 [2M+Na]⁺; [α]_(D) ²² −32.1° (c=2.18, CHCl₃); δ_(H) (500MHz, CDCl₃) mixture of rotamers major:minor 2:1; 2.29 (0.33H, d, J=3.31Hz, OH minor), 2.36 (0.66H, dd, J=13.57 and 9.43 Hz, 1×CHCH₂Ph major),2.44-2.62 (1.66H, m, CHCH₂Ph minor and CbzNCH₂CH), 2.64 (0.66, dd,J=13.58 and 6.62 Hz, 1×CHCH₂Ph major), 3.15 (0.66H, brs, OH major),3.29-3.38 (1H, m, 1×CbzNCH₂), 3.44 (0.66H, d, J=11.19 Hz, 1×CbzNCH₂major), 3.57 (0.33H, d, J=11.28 Hz, 1×CbzNCH₂ minor), 3.67 (0.33H, dd,J=9.93 and 2.34 Hz, 1×OCH₂CHOH minor), 3.71 (0.66H, dd, J=9.80 and 3.33Hz, 1×OCH₂CHOH major), 3.89 (0.33H, dd, J=9.97 and 4.31 Hz, 1×OCH₂CHOHminor), 3.96 (0.66H, dd, J=9.80 and 4.81 Hz, 1×OCH₂CHOH major), 4.13(0.33H, d, J=4.68 Hz, CbzNCH minor), 4.20 (0.66H, d, J=4.80 Hz, CbzNCHmajor), 4.32 (0.33H, brs, OCH₂CHOH minor), 4.43 (0.66H, m, OCH₂CHOHmajor), 4.47 (1H, d, J=4.74 Hz, CbzNCH₂CHCH), 5.05-5.25 (2H, m, CH₂Ph),7.05-7.38 (10H, m, Cbz CH); δ_(C) (125 MHz, CDCl₃) 37.199/37.406(CH₂Ph), 44.588/45.254 (CbzNCH₂CH), 49.193/49.707 (CbzNCH₂),67.148/67.340 (CH₂Ph), 68.403/69.363 (CbzNCH), 74.163/74.215 (OCH₂CHOH),76.299/77.194 (OCH₂CHOH), 85.457/86.287 (CbzNCH₂CHCH), 126.475, 127.855,127.957, 128.146, 128.306, 128.525, 128.574, 128.715 and 128.856,(aromatic CH), 136.385 (Cbz aromatic quaternary) 138.726/138.826(aromatic quaternary), 154.476/155.421 (Cbz C═O).

Preparation of (3R,3aR,6S,6aR)-(9H-Fluoren-9-yl)methyl6-benzyl-3-hydroxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate(2c′: R¹=Bz)

Methanol (4 mL) was added dropwise to a mixture of 10% palladium oncharcoal (40 mg) and alcohol (125) (312 mg, 0.884 mmol) under anatmosphere of argon whilst chilling with iced water. The argon wasreplaced by hydrogen then the suspension was stirred for 2.25 hours. Thehydrogen was replaced by argon then ethanol (4 mL) added beforefiltering through celite in vacuo. The filter cake was washed withethanol (10 mL) then the solvents removed in vacuo from the filtrate.The residue was azeotroped with diethyl ether (3×5 mL) to obtain thecrude aminoalcohol (126) which was used without further purification.

A solution of sodium carbonate (197 mg, 1.86 mmol) in water (2.5 mL) wasadded whilst stirring to a solution of aminoalcohol (126) (assumed to be0.884 mmol) in 1,4-dioxan (1.25 mL). A solution of9-fluorenylmethoxycarbonyl chloride (240 mg, 0.928 mmol) in 1,4-dioxan(1.25 mL) was added over 10 minutes at 0° C. then the mixture stirredfor 50 minutes then dichloromethane (25 mL) was added and the mixturewashed with water (25 mL). The aqueous layer was re-extracted withdichloromethane (2×10 mL) then the combined organic layers dried(Na₂SO₄), filtered and reduced in vacuo to leave a colourless oil (<620mg). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 10:90 to 50:50 gave alcohol (2c′: R¹=Bz) (365mg, 94%) as a white solid. TLC (R_(f)=0.40, EtOAc:heptane 2:1),analytical HPLC single main peak, R_(t)=20.099 min., HPLC-MS 442.2[M+H]⁺, 464.2 [M+Na]⁺, 905.3 [2M+Na]⁺; [α]_(D) ²² −26.3° (c=1.902,CHCl₃); δ_(C) (125 MHz, CDCl₃) 37.131/37.323 (CHCH₂Ph), 44.315/45.112(FmocNCH₂CH), 47.296/47.647 (Fmoc CH), 49.141/49.368 (FmocNCH₂),65.494/67.278 (Fmoc CH₂), 68.581/69.354 (FmocNCH), 73.813/74.082(OCH₂CHOH), 76.319/76.699 (OCH₂CHOH), 85.411/85.943 (FmocNCH₂CHCH),119.909, 119.932, 119.992, 120.001, 124.466, 124.574, 124.909, 124.961,126.405, 126.529, 127.022, 127.434, 127.741, 127.898, 127.906, 128.501,128.660, 128.795 and 128.841 (aromatic CH), 138.725/138.857 (phenylquaternary), 141.313, 141.438, 143.717, 143.739, 143.943 and 144.034(Fmoc quaternary), 154.308/155.377 (Fmoc C═O).

Preparation of (3aS,6S,6aR)-(9H-Fluoren-9-yl)methyl6-benzyl-3-oxotetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (2d′:R¹=Bz)

Dess-Martin periodinane (663 mg, 1.565 mmol) was added to a stirredsolution of alcohol (2c′: R¹=Bz) (345 mg, 0.782 mmol) in dichloromethane(10 mL) under an atmosphere of argon. The mixture was stirred for 2hours then diluted with dichloromethane (40 mL). The organic phase waswashed with a mixture of saturated aqueous sodium bicarbonate and 0.2Msodium thiosulphate solution (1:1, 40 mL), then saturated aqueous sodiumbicarbonate (40 mL), then brine (40 mL), then dried (Na₂SO₄), filteredand reduced in vacuo to leave a residue. Flash chromatography oversilica, eluting with ethyl acetate:heptane mixtures 10:90 to 35:65 gaveketone (2d′: R¹=Bz) (318 mg, 93%) as a white solid. TLC (R_(f)=0.65,EtOAc:heptane 2:1), analytical HPLC broad main peak,R_(t)=19.697-21.766, HPLC-MS 440.2 [M+H]⁺, 462.2 [M+Na]⁺, 901.3[2M+Na]⁺; [α]_(D) ²² −116.3° (c=1.76, CHCl₃); δ_(H) (500 MHz, CDCl₃)mixture of rotamers approximately 6:5, 2.43-2.65 (3H, m, CHCH₂Ph),3.46-3.53 (1.55H, m, 1×FmocNCH₂ minor and 2×FmocNCH₂ major), 3.70(0.45H, dd, J=8.97 and 1.78 Hz, 1×FmocNCH₂ minor), 3.89-3.94 (1H, m,1×OCH₂C═O), 3.98-4.15 (1.45H, m, FmocNCH minor and 1×OCH₂C═O), 4.19-4.24(0.55H, m, Fmoc CH major), 4.25-4.35 (1H, m, FmocNCH major and Fmoc CHminor), 4.47-4.64 (3H, m, Fmoc CH₂ and FmocNCH₂CHCH), 7.08-7.77 (13H,aromatic CH); δ_(C) (125 MHz, CDCl₃); 36.690 (CH₂Ph), 44.733/45.276(CHCH₂Ph), 47.30 (Fmoc CH), 49.69/49.87 (FmocNCH₂), 60.89/61.28(FmocNCH), 67.54/67.97 (Fmoc CH₂), 70.28/70.36 (OCH₂C═O), 84.94/85.90(FmocNCH₂CHCH), 119.88, 119.96, 124.94, 125.20, 125.40, 126.76, 127.05,127.07, 127.70, 127.81, 128.71, 128.79 and 128.85 (aromatic CH), 138.21(phenyl quaternary), 141.31, 143.64, 143.93, and 144.43 (Fmocquaternary), 155.02/155.27 (Fmoc C═O), 208.68/208.79 (ketone C═O).

Preparation of(S)-3-((S)-2-azido-2-(1-methylcyclopentyl)acetyl)-4-benzyloxazolidin-2-one (134)

A solution of potassium bis(trimethylsilyl)amide (0.5M in toluene, 34.4mL, 17.2 mmol) was added over 8 minutes to a stirred solution of(S)-4-benzyl-3-(2-(1-methylcyclopentyl)acetyl)oxazolidin-2-one (2.39 g,7.92 mmol) (133) in tetrahydrofuran (60 mL) at −70° C. under anatmosphere of argon. The solution was stirred at −70° C. for 20 minutesthen a solution of trisyl azide (6.33 g, 20.5 mmol) in tetrahydrofuran(40 mL, precooled to −70° C.) was added via cannula over 15 minutes. Themixture was stirred at −70° C. for 1 hour, then stirred at 30° C. for 1h. A saturated aqueous solution of sodium hydrogen carbonate (100 mL)was added then the majority of solvents were removed in vacuo. Theresidue was partitioned between dichloromethane (300 mL) and brine (300mL). The aqueous layer was re-extracted with dichloromethane (2×100 mL)then the combined organic layers were washed with saturated aqueoussodium hydrogen carbonate solution (100 mL), dried (Na₂SO₄), filteredand reduced in vacuo to leave a yellow oil (8.2 g). Flash chromatographyover silica, eluting with ethyl acetate:heptane mixtures 0:100 to 15:85gave desired intermediate (134) as a yellow oil, Yield 2.27 g, 78%. TLC(R_(f)=0.32, EtOAc:heptane 1:3), analytical HPLC, R_(t)=23.56 min.,HPLC-MS 315.2 [M−N₂+H]⁺, 365.1 [M+Na]⁺.

Preparation of tert-butyl(S)-2-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-(1-methylcyclopentyl)-2-oxoethylcarbamate (135)

10% Palladium on charcoal (450 mg) was added to azide (134) (2.23 g)followed by a solution of di-tert-butyl dicarbonate (4.36 g, 20.0 mmol,3.07 eq.) in N,N-dimethylformamide (35 mL) under an atmosphere of argon.The argon was replaced by hydrogen then the mixture was stirred for 2hours before filtering through celite in vacuo. The filter cake waswashed with N,N-dimethylformamide (20 mL) then the solvents removed invacuo from the filtrate (water bath temperature <50° C.). The residuewas dissolved in ethyl acetate (400 mL) then washed with brine (3×100mL), dried (MgSO₄), filtered and reduced in vacuo to leave a dark oil(5.5 g). Flash chromatography over silica, eluting with ethylacetate:heptane mixtures 0:100 to 20:80 gave desired Boc-protectedintermediate (135) as a colourless gum (1.03 g, 38%). TLC (R_(f)=0.38,EtOAc:heptane 1:3), analytical HPLC, R_(t)=22.96 min., HPLC-MS 317.2[M−Boc+2H]⁺, 361.2 [M+2H−^(t)Bu]⁺, 855.4 [2M+Na]⁺.

Preparation of(S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopentyl)acetic acid(136)

Aqueous hydrogen peroxide solution (30% 1.15 mL) was added to a stirredsolution of Boc-protected intermediate (135) (1.02 g, 2.45 mmol) in amixture of tetrahydrofuran (30 mL) and water (9 mL) at 0° C. Lithiumhydroxide monohydrate (128 mg, 3.04 mmol) was added then the mixture wasstirred at 0° C. for 1 h, then overnight at ambient temperature. Afurther aliquot of hydrogen peroxide solution (30% 0.575 mL) was addedfollowed by lithium hydroxide monohydrate (64 mg and stirring continuedat ambient temperature for 3 h. A solution of sodium sulphite (1.87 g)in water (10 mL) was then added followed by aqueous sodium hydrogencarbonate solution (30 mL). The mixture was stirred for 5 minutes thenthe volume reduced by half in vacuo (≧25 mbar, external water bath 25°C.). Water (50 mL) was added then the pH adjusted to ≦2 using 5Mhydrochloric acid. The aqueous phase was, extracted with dichloromethane(4×50 mL), then the combined organic layers were dried (Na₂SO₄),filtered and reduced in vacuo to leave a pale yellow oil. The oil waspartitioned between a solution of sodium carbonate (1.4 g) in water (50mL) and diethyl ether (20 mL). The aqueous layer was re-extracted withdiethyl ether (3×20 mL) then the pH adjusted to ≦2 using 5M hydrochloricacid. The acidified aqueous layer was then extracted with diethyl ether(3×20 mL) then the combined organic layers dried (MgSO₄), filtered andreduced in vacuo to leave acid (136) as a colourless gum (Yield 475 mg,76%). Analytical HPLC, R_(t)=16.74 min., HPLC-MS 156.1 [M−Boc+2H]⁺,220.1 [M+2H−^(t)Bu]⁺, 537.3 [2M+Na]⁺; [α]_(D) ²¹ +27.2° (c=2.576,CHCl₃). δ_(H) (500 MHz, CDCl₃) 0.90 (3H, s, CH₃C), 1.35-1.45+1.61-1.81(8H, m, 4×CH₂), 1.45 (9H, s, (CH₃)₃C), 4.18 (1H, d, J=9.2, NCH), 5.12(1H, d, J=8.95, NH), 8.7-10.0 (1H, b, COOK); δ_(C) (125 MHz, CDCl₃)22.26/22.41/22.66 (CH₃C), 23.85/24.08/24.32/24.61/25.91+36.88/36.94(4×CH₂), 28.30 ((CH₃)₃C), 45.03/45.61 (CH₃C), 60.84 (NHCH), 79.98((CH₃)₃C), 155.76/156.46 (NHC═O), 177.04 (CHC═O).

Solid Phase Chemistry

Fmoc-ketone building blocks (2c, 2c′, 2d, 2d′) may be utilised in asolid phase synthesis of example inhibitors (1-30 and 38-42) of generalformula I. The methods used were directly analogous to those describedin detail in WO02057270, utilising the4-{[(Hydrazinocarbonyl)amino]methyl}cyclohexane carboxylic acidtrifluoroacetate based linker, solid phase lanterns (ex Mimotopes),standard Fmoc chemistries or Hoc chemistry with graduated acidolyticdeprotection (see WO04007501, pg 309 (iv)) and acidolytic cleavagefollowed by semi-preparative HPLC purification (see WO02057270 pg124-127 for full generic details). Alternative EXAMPLES of the inventioncan readily be prepared by the general methods detailed in WO02057270through use of the appropriately derivatised R⁹—COOH carboxylic acid andstandard uronium activation techniques.

Example 1N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.74 min, 457.3 [M+H]⁺, 475.3 [M+H+18]⁺.

Example 2N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.72 min, 457.2 [M+H]⁺, 475.3 [M+H+18]⁺, 935.3 [2M+H]⁺.

Example 3N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.63 min, 457.2 [M+H]⁺, 475.2 [M+H+18]⁺, 935.3 [2M+H]⁺.

Example 4N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.87 min, 469.3 [M+H]⁺, 487.3 [M+H+18]⁺, 959.4 [2M+Na]⁺.

Example 5N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.52 min, 457.2 [M+H]⁺, 475.2 [M+H+18]⁺, 935.4 [2M+H]⁺.

Example 6N—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.33 min, 457.2 [M+H]⁺, 475.2 [M+H+18]⁺, 935.4 [2M+H]⁺.

Example 7N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.59 min, 469.2 [M+H]⁺, 487.3 [M+H+18]⁺, 959.4 [2M+Na]⁺.

Example 8N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.07 min, 493.2 [M+H]⁺, 511.3 [M+H+18]⁺, 1007.3 [2M+Na]⁺.

Example 9N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.87 min, 493.2 [M+H]⁺, 511.2 [M+H+18]⁺, 1007.3 [2M+H]⁺.

Example 10N-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.00 min, 493.2 [M+H]⁺, 511.2 [M+H+18]⁺, 1007.3 [2M+H]⁺.

Example 11N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.15 min, 505.2 [M+H]⁺, 523.2 [M+H+18]⁺, 1031.3 [2M+H]⁺.

Example 12N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.08 min, 493.2 [M+H]⁺, 511.3 [M+H+18]⁺, 1007.3 [2M+Na]⁺.

Example 13N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.00 min, 493.2 [M+H]⁺, 511.2 [M+H+18]⁺, 1007.3 [2M+H]⁺.

Example 14N-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.59 min, 493.2 [M+H]⁺, 511.2 [M+H+18]⁺, 1007.3 [2M+H]⁺.

Example 15N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aR)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.16 min, 505.2 [M+H]⁺, 523.2 [M+H+18]⁺, 1031.3 [2M+H]⁺.

Example 16N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.46 min, 270.7 [M+2H]²⁺, 540.3 [M+H]⁺, 558.3 [M+H+18]⁺.

Example 17N—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.67 min, 576.2 [M+H]⁺, 594.2 [M+H+18]⁺.

Example 18N—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.64 min, 286.6 [M+2H]²⁺, 576.2 [M+H]⁺, 594.2 [M+H+18]⁺.

Example 19N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.53 min, 276.2 [M+2H]²⁺, 552.2 [M+H]⁺, 570.2 [M+H+18]⁺.

Example 20N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.77 min, 294.7 [M+2H]²⁺, 588.2 [M+H]⁺, 606.2 [M+H+18]⁺.

Example 21N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.64 min, 294.6 [M+2H]²⁺, 588.2 [M+H]⁺, 606.2 [M+H+18]⁺.

Example 22N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)benzamide

HPLC-MS R_(t)=4.28 min, 270.7 [M+2H]²⁺, 540.2 [M+H]⁺, 558.3 [M+H+18]⁺,1101.3 [2M+H]⁺.

Example 23N—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.93 min, 471.3 [M+H]⁺, 489.3 [M+H+18]⁺, 963.4 [2M+H]⁺.

Example 24N—((S)-1-((3aS,6R,6aH)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.28 min, 485.3 [M+H]⁺, 503.3 [M+H+18]⁺, 991.5 [2M+H]⁺.

Example 25N—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.69 min, 471.3 [M+H]⁺, 489.3 [M+H+18]⁺, 963.4 [2M+H]⁺.

Example 26N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.98 min, 485.3 [M+H]⁺, 503.3 [M+H+18]⁺, 991.5 [2M+H]⁺.

Example 27N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.22 min, 483.3 [M+H]⁺, 501.3 [M+H+18]⁺, 987.3 [2M+Na]⁺.

Example 28N—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.55 min, 497.3 [M+H]⁺, 515.3 [M+H+18]⁺, 1015.4 [2M+Na]⁺.

Example 29N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.95 min, 483.3 [M+H]⁺, 501.3 [M+H+18]⁺, 9873 [2M+Na]⁺.

Example 30N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.24 min, 497.3 [M+H]⁺, 515.3 [M+H+18]⁺, 1015.4 [2M+Na]⁺.

Example 38N-((1S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aR)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.29 min, 497.3 [M+H]⁺, 515.3 [M+H+18]⁺.

Example 39N—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.97 min, 495.3 [M+H]⁺, 513.3 [M+H+18]⁺.

Example 40N—((S)-2-((3aS,6S,6aR)-6-benzyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.74 min, 545.3 [M+H]⁺, 563.3 [M+H+18]⁺.

Example 41N—((S)-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=4.09 min, 483.3 [M+H]⁺, 501.3 [M+H+18]⁺, 987.4 [2M+Na]⁺.

Example 42N—((S)-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide

HPLC-MS R_(t)=3.64 min, 483.4 [M+H]⁺, 501.4 [M+H+18]⁺.

Solution Phase Syntheses.

Alternatively, EXAMPLES of the invention may be prepared by traditionalsolution phase organic chemistry techniques for example from buildingblock (107) (3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-olor building block (109)(3R,3aR,6S,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol or thecorresponding hydrochloride salt.

Alternative Preparation of.N—((S)-3,3-dimethyl-1-43aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide(EXAMPLE 3) (i) Preparation of tert-butyl(S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate

4-Methylmorpholine (1.062 mL, 9.7 mmol) was added to a suspension of2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU, 1839 mg, 4.85 mmol), 1-hydroxybenzotriazole (654 mg, 4.85 mmol)and (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (1.125 g,4.85 mmol) in dimethylformamide (5 mL). The mixture was stirred for 5minutes before adding to(3R,3aR,6R,6aR)-6-methylhexahydro-2H-furo[3,2-b]pyrrol-3-ol (107)(prepared as above with appropriate scaling of quantities, assume 4.62mmol). The mixture was stirred for 16 hours then the solvents removed invacuo. The crude product was dissolved in DCM (75 mL) then washed with(75 ML each) sat. NaHCO₃, 0.01N HCl, brine and the organic layer driedover Na₂SO₄. The mixture was filtered to leave a tan oil (2.20 g). Flashchromatography over silica, eluting with ethyl acetate:pentane mixtures15:85 to 50:50 gave desired alcohol as a white solid (1.45 g,contaminated with tetramethylurea). Analytical HPLC main peak,R_(t)=11.94 min., HPLC-MS 301.2 [M+2H−^(t)Bu]⁺, 357.2 [M+H]⁺, 379.2[M+Na]⁺, 735.5 [2M+Na]⁺.

(ii) Preparation of(S)-2-amino-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethylbutan-1-one.hydrochloride

A solution of 4N HCl in 1,4-dioxan (20 mL, 80 mmol) was added totert-butyl(S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-ylcarbamate(1.43 g, assuming 4.0 mmol). The solution was stirred for 90 minutesthen the solvents were removed in vacuo and the residue azeotroped withTBME (3×25 mL) to leave(S)-2-amino-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethylbutan-1-one,hydrochloride as a purple crystalline solid which was used withoutfurther purification. HPLC-MS 257.2 [M+H]⁺.

(iii) Preparation of(N—((S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide

4-Methylmorpholine (0.92 mL, 8.4 mmol) was added to a suspension of2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU, 1.593 g, 4.2 mmol), 1-hydroxybenzotriazole (567 mg, 4.2 mmol) and4-(4-methylpiperazin-1-yl)benzoic acid (924 mg, 4.2 mmol) in DMF (5 mL).The suspension was sonicated for 1 minute then stirred for 5 minutesbefore adding toS)-2-amino-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethylbutan-1-one.hydrochloride (assume 4.0 mmol). The reaction was stirred for 6 hoursthen the majority of solvents removed in vacuo. The residue wasdissolved in dichloromethane (75 mL) and washed with saturated sodiumhydrogen carbonate solution (2×75 mL) The aqueous phase was extractedwith dichloromethane (2×25 mL) then the combined organic layers washedwith brine (75 mL), then dried (Na₂SO₄), filtered and reduced in vacuoto give a tan solid (Yield 1.70 g). Flash chromatography over silica,eluting with methanol:dichloromethane mixtures 1:99 to 10:90 gavedesired alcohol as an off-white solid (1.53 g, 3.44 mmol, 88%). TLC(R_(f)=0.18-0.29 double spot, MeOH:CH₂Cl₂ 10:90), analytical HPLC mainpeak, R_(t)=9.40 min., HPLC-MS 459.3 [M+H]⁺, 939.4 [2M+Na]⁺; [α]_(D)^(22.0) +25.0° (c=2.0, CHCl₃);

(iv) Oxidation to Example 3

Dess-Martin periodinane (2.88 g, 6.8 mmol) was added to a stirredsolution of(N—((S)-1-((3R,3aR,6R,6aR)-3-hydroxy-6-methyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide(1.56 g, 3.40 mmol) in DCM (30 mL) under an atmosphere of argon. Themixture was stirred for 19 hours then diluted with dichloromethane (40mL). The organic phase was washed with aqueous sodium hydroxide solution(1M, 40 mL) then the aqueous extracted with DCM (2×25 mL). The organiclayer was washed with aqueous sodium hydroxide solution (1M, 40 mL) then1:1 sat. NaHCO₃/brine (40 mL), then dried (Na₂SO₄), filtered and reducedin vacuo to leave the desired ketone as a pale orange solid (1.54 g,3.36 mmol, 99.1%). Analytical HPLC main peak, R_(t)=9.17 min., HPLC-MS457.2 [M+H]⁺, 475.2 [M+H₂O+H]⁺, 935.3 [2M+Na]⁺.

(v) Preparation of Hydrochloride Salt

N—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide(1.51 g, 3.33 mmol) was dissolved in acetonitrile (55 mL) and 0.1N HCl(43.3 mL, 4.33 mmol, 1.3 eq.) added. The mixture was spun-frozen thenlyophilised to give an orange crystalline solid (Yield 2.88 g). [α]_(D)^(22.0) −12.0° (c=1.04, CHCl₃); δ_(C) (125 MHz, d₆-DMSO); 10.13 (CH₃CH),26.59 ((CH₃)C), 34.76 ((CH₃)C), 38.04 (CH₃CH), 41.95 (CH₃N), 44.52/44.54(NCH₂), 51.86/52.39 (CH₃NCH₂CH₂N), 58.30 (NHCH), 62.09 (NCHCH), 70.74(CHOCH₂CH), 82.25 (CH₃CHCH), 114.25/129.27 (CH-aryl), 124.27/151.17(Daryl), 166.49 (CONH), 170.07 (CON), 209.91 (C(O)CH₂).

Formation of Example Hydrochloride Salt

EXAMPLE ketone (free base) (1 mmol) was dissolved in acetonitrile (16.7mL) and standardised 0.1N HCl (1.3 eq, 13.0 mL) was added. The mixturewas frozen and lyophilised to leave the EXAMPLE hydrochloride salt as asolid.

Example A Assays for Cysteine Protease Activity

The compounds of this invention may be tested in one of a number ofliterature based biochemical assays that are designed to elucidate thecharacteristics of compound inhibition. The data from these types ofassays enables compound potency and the rates of reaction to be measuredand quantified. This information, either alone or in combination withother information, would allow the amount of compound required toproduce a given pharmacological effect to be determined.

In Vitro Cathepsin Ki Inhibition Measurements

Stock solutions of substrate or inhibitor were made up to 10 mM in 100%dimethylsulfoxide (DMSO) (Rathburns, Glasgow, U.K.) and diluted asappropriately required. In all cases the DMSO concentration in theassays was maintained at less than 1% (vol./vol.). The equilibriuminhibition constants (K_(i) ^(ss)) for each compound were measured understeady-state conditions monitoring enzyme activity as a function ofinhibitor concentration. The values were calculated on the assumption ofpure competitive behaviour (Cornish-Bowden, A. Fundamentals of enzymekinetics Portland Press; 1995, 93-128.). Human recombinant cathepsin K(0.25 nM final; B. Turk, Josef, Stefan Institute, Ljubljana, Slovenia),was routinely assayed in 100 mM sodium acetate; pH 5.5 containing 1 mMEDTA, 10 mM L-cysteine and 1.8 μM Z-Leu-Arg-AMC ([S]=K_(M)).

Measurement of the Apparent Macroscopic Binding (Michaelis) Constants(K_(M) ^(app)) for Substrates

The apparent macroscopic binding constant (K_(M) ^(app)) for eachsubstrate was calculated, from the dependence of enzyme activity as afunction of substrate concentration. The observed rates were plotted onthe ordinate against the related substrate concentration on the abscissaand the data fitted by direct regression analysis (Prism v 3.02;GraphPad, San Diego, USA) using Equation 1 (Cornish-Bowden, A.Fundamentals of enzyme kinetics Portland Press; 1995, 93-128.).

$\begin{matrix}{v_{i} = \frac{V_{\max}^{app} \cdot \left\lbrack S_{o} \right\rbrack}{\left\lbrack S_{o} \right\rbrack + K_{M}^{app}}} & (1)\end{matrix}$

In Equation 1 ‘v_(i)’ is the observed initial rate, ‘V_(max) ^(app)’ isthe observed maximum activity at saturating substrate concentration,‘K_(M) ^(app)’ is the apparent macroscopic binding (Michaelis) constantfor the substrate, ‘[S_(o)]’ is the initial substrate concentration.

Measurement of the Inhibition Constants

The apparent inhibition constant (K_(i)) for each compound wasdetermined on the basis that inhibition was reversible and occurred by apure-competitive mechanism. The K_(i) values were calculated, from thedependence of enzyme activity as a function of inhibitor concentration,by direct regression analysis (Prism v 3.02) using Equation 2(Cornish-Bowden, A., 1995.).

$\begin{matrix}{v_{i} = \frac{V_{\max}^{app} \cdot \lbrack S\rbrack}{\lbrack S\rbrack + \left\{ {K_{M}^{app} \cdot \left( {\lbrack I\rbrack/K_{i}} \right)} \right\}}} & (2)\end{matrix}$

In Equation 2 ‘v_(i)’ is the observed residual activity, ‘V_(max)^(app)’ is the observed maximum activity (i.e. in the absence ofinhibitor), ‘K_(M) ^(app)’ is the apparent macroscopic binding(Michaelis) constant for the substrate, ‘[S]’ is the initial substrateconcentration, ‘K_(i)’ is the apparent dissociation constant and ‘[I]’is the inhibitor concentration.

In situations where the apparent dissociation constant (K_(i) ^(app))approached the enzyme concentrations, the K_(i) ^(app) values werecalculated using a quadratic solution in the form described by Equation3 (Morrison, J. F. Trends Biochem. Sci., 7, 102-105, 1982; Morrison, J.F. Biochim. Biophys. Acta. 185, 269-286, 1969; Stone, S. R. andHofsteenge, J. Biochemistry, 25, 4622-4628, 1986).

$\begin{matrix}{v_{i} = \frac{F\left\{ {E_{o} - I_{o} - K_{i}^{app} + \sqrt{\left( {E_{o} - I_{o} - K_{i}^{app}} \right)^{2} + {4 \cdot K_{i}^{app} \cdot E_{o}}}} \right\}}{2}} & (3) \\{K_{i}^{app} = {K_{i}\left( {1 + {\left\lbrack S_{o} \right\rbrack/K_{M}^{app}}} \right)}} & (4)\end{matrix}$

In Equation 3 ‘v_(i)’ is the observed residual activity, ‘F’ is thedifference between the maximum activity (i.e. in the absence ofinhibitor) and minimum enzyme activity, ‘E_(o)’ is the total enzymeconcentration, ‘K_(i) ^(app)’ is the apparent dissociation constant and‘I_(o)’ is the inhibitor concentration. Curves were fitted by non-linearregression analysis (Prism) using a fixed value for the enzymeconcentration. Equation 4 was used to account for the substratekinetics, where ‘K_(i)’ is the inhibition constant, ‘[S_(o)]’ is theinitial substrate concentration and ‘K_(M) ^(app)’ is the apparentmacroscopic binding (Michaelis) constant for the substrate (Morrison,1982).

The Second-Order Rate of Reaction of Inhibitor with Enzyme

Where applicable, the concentration dependence of the observed rate ofreaction (k_(obs)) of each compound with enzyme was analysed bydetermining the rate of enzyme inactivation under pseudo-first orderconditions in the presence of substrate (Morrison, J. F., TIBS, 102-105,1982; Tian, W. X. and Tsou, C. L., Biochemistry, 21, 1028-1032, 1982;Morrison, J. F. and Walsh, C. T., from Meister (Ed.), Advances inEnzymol., 61, 201-301, 1988; Tsou, C. L., from Meister (Ed.), Advancesin Enzymol., 61, 381-436, 1988;). Assays were carried out by addition ofvarious concentrations of inhibitor to assay buffer containingsubstrate. Assays were initiated by the addition of enzyme to thereaction mixture and the change in fluorescence monitored over time.During the course of the assay less than 10% of the substrate wasconsumed.

$\begin{matrix}{F = {{v_{s}t} + \frac{\left( {v_{o} - v_{s}} \right)\left\lbrack {1 - {\mathbb{e}}^{({k_{obs} \cdot t})}} \right\rbrack}{k_{obs}} + D}} & (5)\end{matrix}$

The activity fluorescence progress curves were fitted by non-linearregression analysis (Prism) using Eq. 5 (Morrison, 1969; Morrison,1982); where ‘F’ is the fluorescence response, ‘t’ is time, ‘v_(o)’ isthe initial velocity, ‘v_(s)’ is the equilibrium steady-state velocity,‘k_(obs)’ is the observed pseudo first-order rate constant and ‘D’ isthe intercept at time zero (i.e. the ordinate displacement of thecurve). The second order rate constant was obtained from the slope ofthe line of a plot of k_(obs) versus the inhibitor concentration (i.e.k_(obs)/[I]). To correct for substrate kinetics, Eq. 6 was used, where‘[S_(o)]’ is the initial substrate concentration and ‘K_(M) ^(app)’ isthe apparent macroscopic binding (Michaelis) constant for the substrate.

$\begin{matrix}{k_{inact} = \frac{k_{obs}\left( {1 + {\left\lbrack S_{o} \right\rbrack/K_{M}^{app}}} \right)}{\lbrack I\rbrack}} & (6)\end{matrix}$

Compounds of the invention when tested by the above described assaysexhibit cathepsin K inhibitory activity with an in vitro Ki inhibitoryconstant of less than or equal to 100 nM.

Liver Microsomal Incubations:

Human and rat liver microsomes were purchased from BD Gentest (Woburn,Mass., USA) and β-nicotinamide adenine dinucleotide 2′-phosphate reducedtetrasodium salt (NADPH) was purchased from Sigma-Aldrich (Poole,Dorset, UK). All liver microsome incubations were carried out in 50 mMpotassium phosphate buffer at pH 7.4, with a final microsomal proteinconcentration of 0.5 mg/mL. Compounds were taken from 5 mM DMSO stocksolutions and diluted in incubation buffer to give a final concentrationof 25 μM, with a final DMSO concentration of 0.5% v/v. In brief,compounds were added to the incubation buffer along with the livermicrosomes and incubated at 37° C. for 10 minutes. The reaction was theninitiated by the addition of NADPH, previously dissolved in incubationbuffer, to give a final concentration of 1 mM and re-incubated at 37° C.Aliquots were removed at 2 and 60 minutes and quenched with an equalvolume of cold acetonitrile. After mixing vigorously, the precipitatedprotein matter was removed by filtration (Multiscreen Solvinert filterplates, Millipore, Bedford, Mass., USA) and the filtrate analysed byreverse phase HPLC with mass spectrometric detection, using single ionmonitoring of the [M+H]⁺ species. Metabolic turnover was determined bycomparison of peak areas from the ion chromatograms of the parentcompound at 2 and 60 minutes and expressed as percent remaining at 1hour.

Plasma Incubations:

Human and rat plasma were purchased from Innovative Research Inc.(Southfield. Mich., USA). Compounds were taken from 5 mM DMSO stocksolutions and added to plasma, which had previously been incubated at37° C., to give a final concentration of 25 μM and re-incubated.Aliquots were removed at 2 and 60 minutes and quenched with an equalvolume of cold acetonitrile. After mixing vigorously, the precipitatedprotein matter was removed by filtration (Multiscreen Solvinert filterplates, Millipore, Bedford, Mass., USA) and the filtrate analysed byreverse phase HPLC with mass spectrometric detection, using single ionmonitoring of the [M+H]⁺ species. Metabolic turnover was determined bycomparison of peak areas from the ion chromatograms of the parentcompound at 2 and 60 minutes and expressed as percent remaining at 1hour.

Log D Determinations:

Log D_((PBS)) determinations were performed in 96 well microtitre platesusing a miniaturised “shake-flask” method. In brief, compounds weretaken from 10 mM DMSO stock solutions and added to wells containingequal volumes of phosphate buffered saline (10 mM; pH 7.4) (PBS) and1-octanol (Sigma-Aldrich, Poole, Dorset, UK) to give a finalconcentration of 50 μM. The plates were then capped and mixed vigorouslyfor 1 hour on a microtitre plate shaker, after which they were left tostand, allowing the PBS and octanol phases to separate. The PBS layerwas analysed by reverse phase HPLC with mass spectrometric detection,using single ion monitoring of the [M+H]⁺ species. Log D_((PBS)) wasdetermined by comparison of the peak area from the ion chromatogram ofthe compound in the PBS phase with that of a 50 μM standard of the samecompound dissolved in acetonitrile/water (50:50) and calculated usingthe following formula:

${{Log}\; D} = {{Log}\left\lbrack \frac{{AUCstd} - {AUCpbs}}{AUCpbs} \right\rbrack}$

Where AUCstd and AUCpbs are the peak areas from the standard and testion chromatograms respectively. Log D_((PBS)) determinations were alsomade using PBS at pH6.9 and 5.5 by adjusting the pH of the buffer priorto the start of the assay, with 0.1 M HCL.

Human Osteoclast Resorption Assay

Bone resorption was studied using a model where human osteoclastprecursor cells were cultured on bovine bone slices for 9 days andallowed to differentiate into bone-resorbing osteoclasts. The formedmature osteoclasts were then allowed to resorb bone. The assay wasperformed by Pharmatest Services Ltd, Itäinen Pitkakatu 4C, Turku,Finland. After the culture period, bone collagen degradation productswere quantified from the culture medium as an index of bone resorptionInhibitor compounds were added into the cell cultures after thedifferentiation period and their effects on the resorbing activity ofmature osteoclasts were determined. The studies included a baselinegroup without added compounds and a positive control group where apotent cathepsin K inhibitor E-64 was added.

Human peripheral blood monocytes were suspended to culture medium andallowed to attach to bovine bone slices. The bone slices weretransferred into 96-well tissue culture plates containing culture mediumwith appropriate amounts of important growth factors favouringosteoclast differentiation, including M-CSF, RANK-ligand and TGF-β. Thecells were incubated in a CO₂ incubator in humidified atmosphere of 95%air and 5% carbon dioxide at 37° C. At day 7 when osteoclastdifferentiation was complete, the culture medium was replaced withculture medium containing conditions favouring osteoclast activity. Thecell culture was continued for an additional 2 days, during which theformed mature osteoclasts were allowed to resorb bone in the presence ofvehicle, control inhibitor (E64) or test compounds. At the end of theculture, bone collagen degradation products released into the culturemedium were determined using a commercially available ELISA method(CrossLaps® for culture, Nordic Bioscience, Herlev, Denmark) as an indexof bone resorption (see Bagger, Y. Z. et al, J. Bone. Miner. Res. 14(suppl. 1), S370).

In this assay, selected EXAMPLES of the invention exhibit more than 75%inhibition of bone resorption at a concentration of 1000 nM.

Rat Osteoclast Resorption Assay

Bone resorption was studied using a model where mature osteoclastsderived from rat bone were cultured on bovine bone slices for 3 days andallowed to resorb bone in the presence of inhibitor, positive control(E-64) or vehicle. More specifically, tibia, femori and humeri wereremoved from 1 day old rat pups. The endosteal surfaces of the boneswere scraped with a scapelto release osteoclasts into the culture mediumand the osteoclasts were allowed to attach to bovine bone slices. Afterthe culture period, bone collagen degradation products were quantifiedfrom the culture medium as an index of bone resorption. The assay wasperformed by Pharmatest Services Ltd, Itäinen Pitkakatu 4C, Turku,Finland.

In this assay, selected EXAMPLES of the invention exhibit more than 75%inhibition of bone resorption at a concentration of 1000 nM.

Various modifications and variations of the described aspects of theinvention will be apparent to those skilled in the art without departingfrom the scope and spirit of the invention. Although the invention hasbeen described in connection with specific preferred embodiments, itshould be understood that the invention as claimed should not be undulylimited to such specific embodiments. Indeed, various modifications ofthe described modes of carrying out the invention which are obvious tothose skilled in the relevant fields are intended to be within the scopeof the following claims.

TABLE 1 Biological properties for EXAMPLE compounds and prior artcompounds (23) and (45). In vitro Ki (nM) vs EXAMPLE Cath K

87.4 Prior art compound 23 (Quibell, M. et. al. Bioorg. Med. Chem., 13,609- 625, 2005); Prior art compound 10 (Quibell, M. et. al. Bioorg. Med.Chem., 12, 5689-5710, 2004);

8.7 Prior art compound 42 (Quibell, M. et. al. Bioorg. Med. Chem., 13,609- 625, 2005); Prior art compound 45a (Quibell, M. et. al. Bioorg.Med. Chem., 12, 5689-5710, 2004);

2.5

1.5

1.0

0.75

1.1

0.35

1.7

0.8

0.7

0.6

0.45

0.7

4.4

3.2

0.8

0.8

1.2

1.5

0.4

0.45

TABLE 2 Prior art WO-A-02057270 in vitro Ki against recombinant humancathepsin K. Selected compounds of the present invention aresignificantly more potent than those specifically detailed in prior artWO-A-02057270 when assayed in vitro against recombinant human cathepsinK (compare tables 1 and 2). Example No (WO- Ki (nM) vs Human A-02057270)Cathepsin K 1 >20000 2 >50000 3 >4000 4 >100000 5 >100000 6 >200007 >15000 8 390 9 90 10 87 11 1300 12 170 13 560 14 300 15 60 16 110 17235 18 130 19 530 20 390 21 210 22 450 23 >3000 24 >2000 25 620 26 >800027 >20000 28 >2500 29 >17000 30 >100000 31 >1500 32 >16000 33 >3600034 >67000 35 >32000 36 570 37 >3500 38 >4000 39 >7500 40 >3500 41 >4500042 >1500 43 >25000 44 >40000 45 >8500 46 >20000 47 830 48 >6500 49 >600050 >10000 51 >1500 52 >25000 53 200 54 >2000 55 >2000 56 >4000 57 39058 >23000 59 >2000 60 >20000 61 >16000 62 >10000 63 >250 64 >8000 65 10066 >2500 67 >2000 68 >2500 69 >15000 70 >2500 71 >20000 72 >2000073 >35000 74 >40000 75 >50000 76 >10000 77 >100000 78 >2000 79 >20080 >150 81 >50000 82 >50000

The invention claimed is:
 1. A compound of formula (I), or apharmaceutically acceptable salt, or hydrate thereof,

wherein: one of R¹ and R² is H, and the other is selected fromC₁₋₈-alkyl, C₂₋₈-alkynyl, C₃₋₆-cycloalkyl and C₁₋₈-alkyl-C₅₋₁₀-aryl; R³is selected from tert-butylmethyl, iso-propylmethyl, sec-butyl,tert-butyl, cyclopentyl, cyclohexyl and 1-methylcyclopentyl; R⁹ isselected from the following:

wherein: R⁴ is selected from C₁₋₈-alkyl and C₃₋₈-cycloalkyl.
 2. Acompound according to claim 1 wherein said compound is of formula Ia

wherein R¹, R², R³ and R⁹ are as defined in claim
 1. 3. A compoundaccording to claim 1 wherein one of R¹ and R² is H, and the other isselected from methyl, ethyl, propyl, iso-propyl, tert-butyl,cyclopropyl, cyclopropylmethyl, iso-propylmethyl, tert-butylmethyl,CH₂OH, CH₂OMe, CH₂OCH₂Ph, CH₂Ph, CH₂F and CHF₂.
 4. A compound accordingto claim 1 wherein one of R¹ and R² is H, and the other is C₁₋₈-alkyl.5. A compound according to claim 1 wherein one of R¹ and R² is H, andthe other is selected from methyl, ethyl, iso-propyl and CHF₂.
 6. Acompound according to claim 1 wherein R³ is selected fromtert-butlmethyl, iso-proplmethyl, sec-butyl, tert-butyl, cyclopentyl andcyclohexyl.
 7. A compound according to claim 1 wherein R³ is cyclopentylor tert-butyl.
 8. A compound according to claim 1 wherein R⁹ is:

and R⁴ is C₁₋₈-alkyl.
 9. A compound according to claim 1 wherein R⁴ isselected from methyl, ethyl and propyl.
 10. A compound according toclaim 1 wherein R⁹ is:

where W is halogen or tosyl.
 11. A compound according to claim 1 whichis selected from the following:N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamideN—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamideN—((S)-4-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)—((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamideN-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamideN-((2S,3S)-3-methyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S))-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S))-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6R,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6R,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamideN—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamideN—((S)-4-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,S6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)—((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-4,4-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)benzamideN-((2S,3S)-3-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)benzamideN-((2S,3S)-3-methyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S))-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S))-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)—((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-oxo-1-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)pentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamide4-(4-ethylpiperazin-1-yl)-N—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-tert-butyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)benzamideN—((S)-1-cyclohexyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-propylpiperazin-1-yl)benzamide.12. A compound according to claim 1 which is selected from thefollowing:N—((S)-4-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-3-methyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-propylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-4-methyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-3,3-dimethyl-1-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN-((2S,3S)-1-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-(difluoromethyl)-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6R,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-ethyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-isopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-oxo-2-((3aS,6S,6aR)-3-oxo-6-propyldihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)ethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-1-cyclopentyl-2-((3aS,6S,6aR)-6-cyclopropyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-benzyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideN—((S)-2-((3aS,6S,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH))-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamideandN—((S)-2-((3aS,6R,6aR)-6-methyl-3-oxodihydro-2H-furo[3,2-b]pyrrol-4(5H,6H,6aH)-yl)-1-(1-methylcyclopentyl)-2-oxoethyl)-4-(4-methylpiperazin-1-yl)benzamide.13. A pharmaceutical or veterinary composition comprising a compoundaccording to claim 1 and a pharmaceutically acceptable or veterinarilyacceptable diluent, excipient and/or carrier.
 14. A process forpreparing a pharmaceutical or veterinary composition, said processcomprising admixing a compound according to claim 1 with apharmaceutically acceptable or veterinarily acceptable diluent,excipient and/or carrier.
 15. The compound according to claim 1, whereinone of R¹ and R² is H, and the other is C₂₋₈-alkynyl.